2009 AnnuAl RepoRt 2009 AnnuAl RepoRt - Ciberdem

2009 Annual Report 

CIBERDEM 

Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas 

Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders


CIBERDEM 


Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders

Contents 

Prologue . ............................................................................4 

Letter from the Scientific Director . ............................................................5 

Management report . .......................................................................6 

About CIBERDEM . ........................................................................7 

Strategic research initiatives . ...............................................................10 

Transversal research projects . .............................................................12 

Technological platforms . .................................................................14 

Project management . ...................................................................18 

Training programme . ....................................................................19 

Outreach activities . .....................................................................21 

Facts and figures . ........................................................................24 

Research . ...........................................................................30 

Transversal research projects: CIBERDEM projects and di@bet.es Study . ..............................32 

Area 1: Insulin signalling and resistance. Role in the onset of diabetes . ................................40 

Area 2: Dyslipidaemia, metabolic syndrome and microvascular complications of diabetes . ..................66 

Area 3: Islet dysfunction, destruction and regeneration. Autoimmunity. Impact on the pathogenesis of diabetes . .106 

Epilogue . ...........................................................................148 

Principal Investigator index . ...............................................................149 

Keyword index . .........................................................................151 

Original articles index . ...................................................................153

Prologue

Letter from the Scientific Director 

The Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders is already in its third 

year of activity. This second report provides ample evidence that the volume of joint projects has risen, the 

number of joint publications has increased and their quality has improved. Some of the successes achieved may 

be relevant for the health of people suffering from diabetes, and this means that the efforts of the researchers 

who work at CIBERDEM have a double value: health and social, as well as economic. Our initial goals will be 

expanded over the coming years, since CIBERDEM is running several relevant projects, some of which may have 

an important impact as a reference in the treatment of diabetes. Clinical researchers take part in all of them and 

in some senses we might say that the culture of cooperation has made a deep impression on all of us. 

Diabetes research in Europe has its own roadmap and we at CIBERDEM are not unconnected with it. On 

the contrary, we expect to position ourselves as leaders due to our efforts in promoting translational research 

into diabetes. This statement might sound pretentious in the period of economic crisis which we are currently 

undergoing, but it is not. Now is possibly not the moment to grow, but it is the moment to consolidate, to be more 

efficient, to position ourselves for a new leap forward when an improved economic situation allows it. To this end, 

we are supporting new initiatives in fundraising and collaborating with private institutions in synergy with all the 

centres in the consortium. 

We know that now, more than at any other time, we need imaginative solutions and we intend to find them because 

we are sure that the project deserves it: our objectives are clearly defined and the programme is ideally placed to 

obtain them. We know that we can count on the enthusiasm of all the CIBERDEM researchers, of the institutions 

in the consortium and especially of the Instituto de Salud Carlos III (ISCIII). 

So, I would like to thank all of them for the triumphs they have obtained in 2009; the merit belongs to them, let us 

wish them all the same success in the future. 

Ramon Gomis 

CIBERDEM Scientific Director 


5

Management report 

CIBERDEM’s second year of existence posed quite a challenge from the perspective of the management of the 

centre. With a budget considerably larger than that of 2008 and that expected for 2010, CIBERDEM has had to 

reconcile the consolidation of the strategic initiatives launched in 2008 with the instigation of other proposals, all 

of them designed to improve the scientific and technical position of the groups. 

Thus, April 2009 marked the start of the 14 transversal projects which come under CIBERDEM’s umbrella. The aim 

of these internal research projects is to encourage translational research within the network, so, the 14 projects 

combine the most basic aspect of research into diabetes and metabolic disorders with possible applications in 

clinical practice. These projects are carried out by a minimum of 3 and a maximum of 8 CIBERDEM groups, which 

fosters internal cooperation and the interchange of ideas. 

Also in 2009, two internal calls for the acquisition of scientific equipment were published. The aim of both calls 

was to provide CIBERDEM research groups with the necessary scientific infrastructure for their work. Thanks 

to the first of the calls, aimed at the acquisition of major scientific equipment, CIBERDEM will be able to boast 

5 leading research groups based in 5 institutions in the network: the Hospital Clínico Universitario de Valencia, 

IBGM-CSIC (Valladolid), IDIBAPS-Hospital Clínic de Barcelona, IIB-CSIC (Madrid) and the Institut d’Investigació 

Sanitària Pere Virgili (Tarragona). The second call was for the acquisition of lesser scientific material; lesser, but 

equally necessary for the correct functioning of the groups. 

Finally, it is worthy of note that in 2009 an effort was made to improve the governance of CIBERDEM. The 

Management Office continued to evolve, improving both its internal management procedures and its communications 

channels with research groups; all of this in order to fulfil our mission of providing researchers with the tools and 

resources they need so that the research carried out in CIBERDEM can be managed in an efficient manner. 

Pastora Martínez Samper 

CIBERDEM Managing Director 

6 CibeRdem

About CIBERDEM 

The Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) 

is a public research consortium which was founded on December 3rd 2007 and is financed by the Instituto de 

Salud Carlos III (ISCIII) and the Ministerio de Ciencia e Innovación (MICINN). 

CIBERDEM is made up of 32 research groups based in different hospitals, universities and research centres 

throughout Spain. The main aim of CIBERDEM is to promote research into diabetes and associated metabolic 

disorders, identifying the genes which predispose to these diseases and the environmental factors which contribute 

to their development; to discover the molecular mechanisms involved in the alteration of insulin secretion and 

signalling; to determine the molecular and cellular mechanisms involved in the formation and destruction of 

pancreatic beta cells; to study strategies for substitution of this cell mass; and to investigate the signals which link 

obesity and diabetes. Of special interest is research into the complications of diabetes and associated metabolic 

disorders. 

CIBERDEM is divided into three research areas: 

Area 1 

Insulin signalling and resistance. 

Role in the onset of diabetes. 

Coordinator: Manuel Benito 

8 research groups 

Area 2 

Dyslipidaemia, metabolic 

syndrome and microvascular 

complications of diabetes. 

Coordinator: Rafael Carmena 


Area 3 

Islet dysfunction, destruction 

and regeneration. Autoimmunity. 

Impact on the pathogenesis of 

diabetes. 

Coordinator: Fàtima Bosch 


The nature, goals and financing of CIBERDEM are enshrined in its statutes, published in the Boletín Oficial del 

Estado (BOE) number 49, of February 26th, 2008. 

The main governing bodies of CIBERDEM are as follows: 

Management Committee 

This is made up of three representatives of the Instituto de Salud Carlos III and one representative from each of 

the other bodies in the consortium; it is the supreme governing body of CIBERDEM and exercises general control 

over the organization. 


7

President 

Joaquín Arenas, Subdirector General de Redes (ISCIII) 

Members 

Mario Vallejo, Consejo Superior de Investigaciones Científicas 

Rubén Moreno Palanques, Fundación Centro de Investigación Príncipe Felipe 

Juan Viña Ribes, Fundación Hospital Clínico Universitario de Valencia 

Emilià Pola, Fundación IDIBELL 

Francesc Xavier Grau, Fundació Institut d’Investigació Sanitària Pere Virgili 

Juan Emilio Feliu, Fundació Institut de Recerca Hospital Universitari Vall d’Hebron 

José Francisco Cañón Campos, Fundación Instituto Mediterráneo para el Avance de la Biotecnología Sanitaria 

Josep Maria Haro Abad, Fundación para la Investigación y Docencia Sant Joan de Déu 

Victoria del Pozo, Fundación Jiménez Díaz 

Margarida Corominas, Fundació Privada Institut de Recerca Biomèdica 

Carmen Garaizar, Fundación Vasca de Innovación e Investigación Sanitarias 

Jaume Kulisevsky, Institut de Recerca Hospital de la Santa Creu i Sant Pau 

Emili Bargalló, Institut d’Investigacions Biomèdiques August Pi i Sunyer 

Elena Andradas, Servicio Madrileño de Salud 

Lluís Ferrer Caubet, Universitat Autònoma de Barcelona 

Xavier Meneses, Universitat de Barcelona 

Carmen Acebal Sarabia, Universidad Complutense de Madrid 

Salvador Viniegra Bover, Universidad Miguel Hernández 

Antonio Villar Notario, Universidad Pablo de Olavide 

Secretary 

Pastora Martínez, CIBERDEM Managing Director 

Permanent Commission 

This consists of the President of the Management Committee, the Scientific Director of the consortium and 

four members representing the other participating institutions. It evaluates the budgets, annual accounts and all 

reports to be submitted to the Management Committee for approval. 

President 

Joaquín Arenas, Subdirector General de Redes (ISCIII) 

Members 

Emilià Pola, Fundación IDIBELL 

Margarida Corominas, Fundació Privada Institut de Recerca Biomèdica 

Antonio Villar Notario, Universidad Pablo de Olavide 

Victoria del Pozo, Fundación Jiménez Díaz 

Secretary 

Pastora Martínez, CIBERDEM Managing Director 

Steering Committee 

This is made up of the Scientific Director, the Coordinator of each research area and the Training Director. It is 

responsible for the scientific activity of CIBERDEM and establishes its plans of action. 

Ramon Gomis, Scientific Director and President of the Steering Committee 

Manuel Benito, Coordinator of Area 1 

Rafael Carmena, Coordinator of Area 2 

Fàtima Bosch, Coordinator of Area 3 

Antonio Zorzano, Training Director 

Pastora Martínez, Managing Director and Secretary of the Steering Committee 

8 CibeRdem

External Scientific Committee 

This is made up of important figures whose professional or scientific contributions to the field of health sciences 

are in tune with the aims and objectives of CIBERDEM. It is the consortium’s scientific advisory body and it 

evaluates each year’s activity as well as that of all the research groups. 

Decio Eizirik, Gene Expresion Unit - Diabetes Research Ctr. VUB, Brussels (Belgium) 

Ele Ferrannini, Institute of Clinical Physiology, Pisa (Italy) 

José M. Ordovas, Human Nutrition Research Center, Boston (USA) 

Francesc Xavier Pi-Sunyer, St. Lukes-Roosevelt Hospital - Endocrinol Diabetes Nutrition, New York (USA) 

Antonio Vidal-Puig, University of Cambridge - Addenbrookes Hospital, Cambridge (UK) 

Management Committee 

External Scientific Committee 

Permanent Commission 

Scientific Director 


Managing Director 

Research Areas 

Technological Platforms 

Management Office 

Area 1 

Biobank 

Area 2 

Metabolomics Platform 

Area 3 

CIBERDEM’s organization chart. 


9

Strategic research initiatives

CIBERDEM is a special case among the nine existing Spanish Biomedical Research Centres (CIBERs) resulting 

from the Ingenio 2010 Programme. It focuses on diabetes and its associated metabolic disorders, but always with 

a view to the transfer of biomedical research to clinical applications and practices. 

Following the strategic research plan which was first implemented in 2008, CIBERDEM’s strategic research 

initiatives (SRIs) were bolstered and augmented in 2009. According to the plan, the objective is to increase 

scientific productivity and enhance the quality of research in this field. CIBERDEM provides its 32 research 

groups with infrastructure and laboratory personnel to carry out their scientific initiatives. It also gives support to 

facilitate collaboration among the researchers in order to reinforce existing synergies and forge new ones; it is 

these synergies which provide the consortium with unique opportunities that would not be possible without the 

existence of CIBERDEM. 

CIBERDEM’s dispersed, network structure means that the SRIs are essential: they provide the consortium with the 

opportunity to join together many individual efforts into cooperative projects yielding high-impact scientific results. 

They allow CIBERDEM to address more complex scientific questions relating to the treatment and prevention of 

diabetes than when the research groups work individually. 

The strategic research initiatives for 2009 were: 

Transversal research projects: In 2009 the call to fund CIBERDEM projects was launched, evaluated, negotiated 

and resolved. As a result, 14 new CIBERDEM translational research initiatives on diabetes were started. In 

addition, the di@bet.es Study, the first national epidemiological study for determining the incidence of diabetes in 

the Spanish population, continued towards its final implementation and presentation of results in 2010. 

Technological platforms: Two scientific platforms laid down a solid scientific base to reinforce the quality of the 

biomedical research that CIBERDEM began in 2008. The CIBERDEM Biobank stores collections of samples 

from diabetic and other metabolic disease patients which are accompanied by their corresponding extensive 

questionnaire (personal clinical data and demographic information together with details of exercise and food 

habits) and are available for the scientific community; also, the Metabolomics Platform offered metabolic services 

to the biomedical and clinical scientific community with the added value of high throughput technology for metabolic 

profiling and the identification of metabolites. 

Research support activity: Project management. During 2009 the aim was to design and implement the European 

Strategic Agenda, mainly providing the research groups with the support to coordinate European projects within 

the 7th Framework Programme, among others, in addition to publicizing the competitive research calls in which 

they could participate. 

Training programme and outreach activities: CIBERDEM worked towards achieving its main goal of promoting 

quality research in diabetes and metabolic disorders by transferring knowledge to and from its researchers and by 

communicating its activities and findings to a variety of audiences. 


11

Transversal research projects 

Introduction 

The priority of CIBERDEM research is diabetes and its 

associated metabolic disorders. The work of each research 

group allows CIBERDEM to achieve many significant 

results, however, in order to accomplish the main 

objectives of the network, the promotion of collaborative 

initiatives inside the consortium is crucial. Strengthening 

collaboration between the research groups brings 

CIBERDEM the possibility of dealing with complex issues 

related to diabetes and associated metabolic disorders 

that the groups independently could not tackle. 

CIBERDEM projects 

Following the strategic research plan started in 2008, during 

2009, the first competitive call to fund new transversal 

projects as strategic research initiatives was launched. It 

was aimed at promoting collaboration between basic and 

clinical researchers and required the participation of a 

minimum of three research groups from the CIBERDEM 

network. The main aim was to reduce the existing distance 

between scientific knowledge and its application 

to patients in the field of diabetes, thus it focused on the 

bench-to-bedside approach. Fourteen CIBERDEM projects 

were selected after a scientific evaluation and negotiation 

with their coordinators. They started in March 2009 

and are planned to continue until December 2010. Thirty 

CIBERDEM research groups started their collaborations 

with the objective of obtaining relevant results. Some of 

them decided to participate in more than one initiative at 

the same time, but always taking into consideration the 

added value they could bring to the project by dint of their 

experience and background. 

IREVAS, NEURONET-DIAB, INGENFRED, MODIAB, 

DOTUM, DIASOBS, GIDIPRED, CHILDBODYFAT, 

ANTIBECELL, LOWHDL, METADIAB, ENDODIAB, 

IODURE and STEMOB began to be implemented during 

2009 which permitted CIBERDEM to achieve its 

goals in translational research (see more on page 33). 

whose objective is to determine the prevalence (known 

and unknown) of type 2 diabetes mellitus, among other 

parameters. Six field work teams compile demographic, 

social and clinical data including relevant information 

such as lifestyle factors (nutritional habits and details 

of individuals’ physical activity) within a representative 

section of the Spanish population. The study will culminate 

in a well-characterized sample collection that 

will be stored in the CIBERDEM Biobank (CIBERDEM 

technological platform). 

The di@bet.es Study aims to provide the Spanish 

heath authorities with the real figures they need to allow 

them to assign the appropriate funds under the 

Spanish healthcare system in order to be able to treat 

diabetic patients in optimum conditions. Furthermore, 

the sample collection available to the scientific community 

via the CIBERDEM Biobank is intended to be used 

to implement scientific projects which need samples 

with related information from a representative section 

of the Spanish population (see more on page 37). ■ 

di@bet.es Study 

Another transversal research project, the di@bet.es 

Study, started in 2008, continued during 2009 and remains 

ongoing. It is a national epidemiological study 

12 CibeRdem

SIMÓ CANONGE 

Rafael 

SIMÓ CANONGE 

Rafael 

SIMÓ CANONGE 

Rafael 

SIMÓ CANONGE 

Rafael 

(a) Collaborations between the research groups of CIBERDEM 

in 2009 taking into consideration CIBERDEM projects, the 

di@bet.es Study and the CIBERDEM Biobank: 

(b) Collaborations resulting from the fourteen CIBERDEM 

projects (2009-2010): 

AREA 3 

MARTIN BERMUDO 

Francisco 

DE PABLO DÁVILA 

Flora 

GOMIS DE BARBARA 

Ramon 

MONTANYA MIAS 

Eduard 

NADAL NAVAJAS 

Ángel 

NOVIALS SARDÀ 

Anna 

VALLEJO FERNÁNDEZ 

Mario 

BENITO DE LAS HERAS 

Manuel R. 

CORREIG BLANCHART 

Xavier 

GOMEZ FOIX 

Ana María 

GUINOVART CIRERA 

Josep Joan 

LORENZO BALADO 

Margarita 

MARTÍNEZ-VALVERDE 

Ángela 

AREA 1 

VILLANUEVA-PEÑACARRILLO 

Marisa 

ZORZANO OLARTE 

Antonio 

AREA 3 


Flora 


Ramon 

MONTANYA MIAS 

Eduard 


Francisco 

NADAL NAVAJAS 

Ángel 


Anna 


Mario 


Manuel R. 


Xavier 

GOMEZ FOIX 

Ana María 


Josep Joan 


Margarita 


Ángela 

AREA 1 


Marisa 


Antonio 

FERRER MARRADES 

Jorge 

BALSINDE RODRIGUEZ 

Jesús 


Jorge 


Jesús 

CASTAÑO GONZALEZ 

Luis 

BURKS 

Deborah J. 

BOSCH TUBERT 

Fàtima 

BLAZQUEZ FERNÁNDEZ 

Enrique 

ALVAREZ ESCOLÁ 

Carmen 

VENDRELL ORTEGA 

Joan J. 

VÁZQUEZ-CARRERA 

Manuel 

SERRANO RIOS 

Manuel 

MASANA MARIN 

Lluís 

IBAÑEZ TODA 

Lourdes 

BLANCO-VACA 

Francisco 

CARMENA RODRIGUEZ 

Rafael 

CASIMIRO-SORIGUER ESCOFET 

Federico J. 

ESCOBAR MORREALE 

Héctor F. 

AREA 2 


Luis 

BURKS 

Deborah J. 

BOSCH TUBERT 

Fàtima 


Enrique 


Carmen 


Joan J. 


Manuel 

SERRANO RIOS 

Manuel 

MASANA MARIN 

Lluís 

IBAÑEZ TODA 

Lourdes 

BLANCO-VACA 

Francisco 


Rafael 


Federico J. 


Héctor F. 

AREA 2 

(c) Collaborations of five CIBERDEM research groups in the 

di@bet.es Study (2008-2010): 

(d) Members of the CIBERDEM Biobank (since 2008): 

AREA 3 


Flora 


Ramon 

MONTANYA MIAS 

Eduard 


Francisco 

NADAL NAVAJAS 

Ángel 


Anna 


Mario 


Manuel R. 


Xavier 

GOMEZ FOIX 

Ana María 


Josep Joan 


Margarita 


Ángela 

AREA 1 


Marisa 


Antonio 

AREA 3 


Francisco 


Flora 


Ramon 

MONTANYA MIAS 

Eduard 

NADAL NAVAJAS 

Ángel 


Anna 


Mario 


Manuel R. 


Xavier 

GOMEZ FOIX 

Ana María 


Josep Joan 


Margarita 


Ángela 

AREA 1 


Marisa 


Antonio 


Jorge 


Jesús 


Jorge 


Jesús 


Luis 

BURKS 

Deborah J. 

BOSCH TUBERT 

Fàtima 


Enrique 


Carmen 


Joan J. 


Manuel 

SERRANO RIOS 

Manuel 

MASANA MARIN 

Lluís 

IBAÑEZ TODA 

Lourdes 

BLANCO-VACA 

Francisco 


Rafael 


Federico J. 


Héctor F. 

AREA 2 


Luis 

BURKS 

Deborah J. 

BOSCH TUBERT 

Fàtima 


Enrique 


Carmen 


Joan J. 


Manuel 

SERRANO RIOS 

Manuel 

MASANA MARIN 

Lluís 

IBAÑEZ TODA 

Lourdes 

BLANCO-VACA 

Francisco 


Rafael 


Federico J. 


Héctor F. 

AREA 2 

The graphs above show the existing collaborations between CIBERDEM research groups through several strategic research initiatives 

of the consortium implemented in 2009 (a) such as the transversal research projects - the fourteen CIBERDEM projects (b) and 

the di@bet.es Study (c) - in addition to the technological platform CIBERDEM Biobank (d) - composed of nine nodes which include 

the Coordinating Node. These relationships demonstrate how the SRIs make CIBERDEM research groups join their efforts regardless 

of their area of activity (Area 1, 2 or 3) or of the nature of research activity they are involved in (basic or clinical). 


13

Technological platform: CIBERDEM Biobank 

Introduction and objectives 

The CIBERDEM Biobank is a novel scientific and technological 

platform which coordinates the collection, processing, 

storage and retrieval of biological samples in the 

field of diabetes and other metabolic diseases, which may 

then be utilized by CIBERDEM research groups and by 

other scientific institutions in their experiments and projects. 

The Biobank, thanks to its experience and expertise 

in this field, also serves as the Metabolic Disease Node 

of the Spanish National DNA Bank and holds one of the 

most important collections of samples of metabolic disorders 

in southern Europe, bringing great added value to 

the biomedical research conducted by CIBERDEM. 

Structured into nodes with multiple collection and processing 

sites, the Biobank allows for the immediate 

storage of samples following blood extraction in order to 

ensure the highest quality possible. Through the centralized 

coordination of sample management, the Biobank 

also ensures the traceability of its samples, as required 

by the recently approved Biomedical Research Act. The 

coordinating node of the CIBERDEM Biobank obtained 

the ISO9001 quality certification in December 2009. 

Scientific services 

The main services provided by the Biobank consist of 

the following: 

Design and management of a large metabolic disorder 

sample collection, involving donor recruitment; data 

registration; informed consent management; serum 

and plasma storage; DNA purification and storage; 

lymphocyte isolation and immortalization; and quality 

management. 

Assurance of traceability. 

Quality control of the stored samples. 

Organization of an internal database for the analysis of 

samples and data. 

Management of sample request proposals through the 

coordination of the Scientific External Committee and 

the Ethics Committee. 

Personalized assistance in sample management. 

Coordinating node 

IDIBAPS, Barcelona: Principal Investigator Ramon 

www.clinicbiobanc.org 

Gomis, Anna Novials Coordinator Anna Bosch 

Associate researcher Laura Brugnara Lab technician 

Anna Morales Lab manager Albert Davins Lab 

technician and quality control manager Roser Mas 

Nurse Laura Tugores 

Nodes 

Hospital Joan XXIII, Tarragona: Principal Investigator 

Joan J Vendrell Research assistant Lluís Gallart Lab 

technician Miriam Campos 

Hospital Sant Joan, Reus: Principal Investigator Lluís 

Masana Research assistant Jordina Saladié, Jordi 

Merino Lab technician Carme Buixadera 

Hospital de Cruces, Barakaldo: Principal Investigator 

Luis Castaño Research assistant and lab manager 

Inés Urrutia Research assistant and dietician Teba 

González 

Hospital Clínico San Carlos, Madrid: Principal 

Investigator Manuel Serrano Ríos PhD student 

Carina Zabena Lab technician Mari Carmen Obiang 

Hospital Civil, Málaga: Principal Investigator Federico 

Soriguer Associate researcher Gemma Rojo 

Research assistant Francisca Linares Nurse María 

José Moreno 

14 CibeRdem

Hospital Clínico, Valencia: Principal Investigator 

Rafael Carmena Associate researcher Javier Chaves 

Research assistant Esther Benito Lab technician 

Verónica González 

Hospital de Sant Pau, Barcelona: Principal Investigator 

Francisco Blanco Associate researcher Jesús Martín 

Lab technician and nurse Cristina Martín 

Facilities 

The Coordinating Node of the Biobank centralizes 

the organization of Biobank sample management and 

is thus endowed with the most advanced technology 

available for this purpose: automated DNA extraction 

platform (Chemagen system, magnetic beads); liquid 

handling station (Tecan EVO150), cell immortalization 

facility (P2 level safety lab); liquid nitrogen tanks; continuous 

monitoring of environmental conditions from 

storage systems; -150ºC freezers; bar-code readers 

and printers; nanodrop spectrophotometer; and nitrogen 

and cryogen free controlled rate freezers. 

The Biobank is equipped with the following facilities 

within each Node, permitting the immediate storage of 

samples taken: -80º C freezers; micronic system for the 

storage of the samples in standardized aliquots; and 

web-based IT infrastructure. 

Achievements in 2009 

2009 was a key year in the consolidation of the CIBERDEM 

Biobank since all the nodes have implemented the use 

of the IT system for specimen logging and management, 

and also because stored samples have been successfully 

used for several research projects, thus proving the 

quality of the established procedures. 

During 2009, the Biobank collected samples from more 

than 1,100 donors affected by the most widespread 

metabolic diseases in Spain: 195 type 1 diabetes; 253 

type 2 diabetes; 123 dyslipidaemias; 183 obesity; and 

382 morbid obesity. As previously established, all of the 

donors completed an extensive questionnaire with personal 

clinical data, demographic information, and exercise 

and food habits, which are currently being entered 

in the Biobank clinical database. These data, together 

with their corresponding samples, represent one of the 

most exhaustive collections available for the study of 

metabolic disorders. Overall, the Biobank freezers and 

tanks stored more than 20,000 aliquots, which were 

coded and registered in a specially designed database. 

Future challenges 

The Biobank plans to expand and improve many of its 

current services and has set itself the following goals 

for the future: the integration in the Biobank of samples 

collected through the «di@bet.es Study», and 

the consolidation of the creation of nodes for coordinating 

new collections, such as the Retina Biobank or 

the Pancreatic Tissue Biobank; the introduction of the 

ISO9000 certificate in the processing nodes; participation 

in the proposal and development of new research 

projects; and the dissemination of the CIBERDEM 

Biobank in the scientific community. ■ 

DNA aliquoting at the Biobank. 


15

Technological platform: Metabolomics Platform 

Introduction and objectives 

Metabolomics is the science that systematically studies 

the unique chemical profile that specific cellular processes 

leave behind. The analysis of metabolomic profiles 

using biological samples such as fluids, tissues, and 

cultured cells helps identify diseases and risk factors, determining 

their corresponding biomarkers. In this sense, 

metabolomics is of particular interest to CIBERDEM in its 

research on diabetes, including different clinical therapies 

and nutritional interventions. The Metabolomics Platform, 

a joint initiative of CIBERDEM and the Universitat Rovira 

i Virgili (URV), seeks to fulfil all the metabolomic needs of 

CIBERDEM research groups by providing them with support 

at every step of metabolomic analysis in their experiments 

from beginning to end: experimental design, sample 

handling, analytical measurements and data processing 

and analysis. Its metabolomic services seek to help 

CIBERDEM groups obtain sound and relevant results that 

may be incorporated into other aspects of their research. 

Scientific services 

The Metabolomics Platform provides quality services to 

CIBERDEM research groups in the field of metabolomics. 

In the experimental design area, the platform offers assistance 

in defining the nature and dimension of the 

sample set in each metabolomic study to be performed, 

with the aim of ensuring sound and significant results 

from the very beginning. 

As regards sample handling, the platform is able to take 

metabolite measurements of almost any biological sample, 

such as body fluids (serum, plasma, urine, cerebrospinal 

fluid, etc.), tissues, biopsies, and cell cultures. 

As far as NMR analysis is concerned, samples are analysed 

using a 600 MHz and/or 500 MHz high resolution 

spectrometer, applying 1D and 2D NMR pulse sequences 

commonly used in the metabolomics field. Finally, 

in the area of data analysis (linking NMR data to biological 

knowledge), data is analysed using the AMIX®, 

Simca-P and Matlab® software packages. These tools 

allow a wide range of multivariate analyses. Metabolite 

identification can be achieved by matching NMR spectra 

with a standard metabolite database (NMRMetaPro® 

database with more than 500 substances). Samples can 

be analysed additionally with GC/MS, HPLC-TOF-MS 

www.metabolomicsplatform.com 

and HPLC-MS-MS platforms and the data obtained are 

processed by Mass Professional Profiler or XCMS software 

packages. These platforms are very useful when 

the object is to find biomarkers associated with a disease 

condition or a drug/diet intervention. 

Coordination 

Principal Investigator Xavier Correig Associate 

researcher Jesús Brezmes, Nicolau Cañellas Research 

assistant Miguel Ángel Rodríguez, Maria Vinaixa, 

Antoni Beltran 

Facilities 

The Metabolomics Platform is located within the Science 

and Technology Services building at the Universitat Rovira 

i Virgili in Tarragona and is equipped with state-of- the-art 

technology including the most sophisticated instruments 

in the NMR and GC/LC/MS fields. The equipment available 

in high field NMR allows high throughput analytical 

measurements of body fluids such as serum or urine, as 

well as tissue analyses and biopsies of human and animal 

samples. 

In terms of HR-NMR equipment, the platform features a 

600 MHz Bruker® Avance III spectrometer fitted with a 

Cryoprobe®. This configuration allows the collection of 

high resolution and high sensitivity measurements with 

a five-fold increase in dynamic range as compared to 

16 CibeRdem

conventional probes. A Samplejet® robot has been joined 

to the spectrometer; this system provides for the storage 

and automatic measurement of hundreds of samples at 

low temperature (down to 4ºC). Using any of the systems, 

a high throughput (i.e. more than 200 measurements per 

day) can be achieved. The platform has also acquired a 

second spectrometer, a 500 MHz Bruker® Avance III with 

an HR-MAS probe, to measure semisolid samples such 

as biopsies, cell cultures, tissues, etc. Both spectrometers 

offer the possibility of programming and controlling the 

sample temperature during each measurement. 

The Platform is fully equipped with MS spectrometers. The 

GC-MS spectrometer, together with the FIEHN, NIST and 

HMDB, allows the detection and identification of hundreds 

of metabolites, especially those which are most volatile in 

a fluid. The HPLC-TOF spectrometer is very flexible and is 

appropriate for measuring a broad range of metabolites at 

very low concentration. The METLIN and HMDB are used 

for the putative identification of metabolites given the exact 

mass. The confirmation of potential biomarkers can be 

done by means of the HPLC-MS-MS platform. 

The possibility of integrating NMR and MS platforms in 

metabolic experiments, makes the platform very robust 

and competitive. 


The Metabolomics Platform, inaugurated in June 2008, 

completed the set-up of important hardware and software 

essential to its NMR-based metabolomic services. 

Analysis protocols for tissues, lipid/aqueous extracts, and 

serum were determined and established. In addition to 

NMR spectrometry, in 2009, facilities for MS spectrometry, 

both gas and liquid, were set up and these may now be 

used routinely in metabolomic experiments. 

Throughout the year, the platform also participated in several 

workshops, courses, seminars and conferences hosted 

by a variety of scientific societies, and it was awarded 

two research grants by the Instituto de Salud Carlos III. 

Finally, efforts were made to publicize the platform’s services 

throughout CIBERDEM and the scientific community 

in general. During 2009, the Metabolomics Platform 

worked on 5 intramural CIBERDEM collaborations in the 

areas of diabetic dyslipaemias, insulin resistance related 

to polycystic ovarian syndrome, and diabetes and exercise. 

In 2009 the Platform started new projects with CIBERDEM 

groups and other institutions in the areas of nutrition and 

health, metabolomic experiments with cell cultures, phenotyping 

of animal models, and so on. 


Important goals set for 2010 include the setting-up of 

methodologies for subclass lipoprotein quantification in 

serum samples by NMR, the full metabolomic characterization 

of pancreatic islets, and the implementation 

of fluxomics techniques based on isotopes. Finally, the 

Metabolomics Platform hopes to increase its overall 

presence in the activities and projects undertaken by 

CIBERDEM research groups. ■ 

Metabolomics Platform NMR-equipment: the 500 and 600 MHz NMR systems can be seen on the left and right, respectively. 


17

Project management 

Introduction 

CIBERDEM, as a Spanish centre, needs to open its 

doors to national, international and intersectorial collaboration. 

One of the main aims of the consortium is 

to promote the participation of its researchers cooperatively 

in national, European and other international calls. 

Only by means of cooperation with other research 

groups in addition to innovative companies, in Spain or 

abroad, will high quality outcomes increase and the impact 

of the research carried out on diabetes and its associated 

disorders be properly felt. 

CIBERDEM is working to obtain additional funding for 

research and more recognition from the scientific community 

by informing researchers of the calls for which 

they are eligible and offering them support to prepare 

their proposals. 

Objectives 

The services that CIBERDEM offers to its researchers 

have the following main objectives: 

To follow the European Strategic Agenda (ESA) designed 

by CIBERDEM with the aim of achieving a 

significant presence in the European Research Area 

(participating in European calls under the European 

Commission’s Seventh Framework Programme, attending 

international events and taking an active role in 

the establishment or modification of European priorities 

among others). 

To inform CIBERDEM researchers about calls and opportunities 

to actively participate in national, European 

or other international programmes through the monthly 

CIBERDEM newsletter. 

To give support to the design and application process 

for CIBERDEM researchers interested in taking part 

in and coordinating a research consortium related to 

CIBERDEM research lines. 

To include Spanish biomedical research, in particular 

CIBERDEM research, in the priorities of health in the 

field of diabetes and associated metabolic disorders. 

Coordination 

Pastora Martínez, CIBERDEM Managing Director, and 

Gemma Pascual, CIBERDEM Project Manager. 


During 2009 the first version of the ESA was designed 

and implemented with the aim of giving CIBERDEM a 

clear goal to strive for. Moreover, many calls and opportunities 

from national, European and other international 

programmes were included in the monthly CIBERDEM 

newsletters in order to offer direct support so that consortium 

members could participate. 

The consortium was presented to the scientific community 

in «From bench to bedside» (Public Service 

Review, Health Issue 18, 2009) written by the Scientific 

Director and the Managing Director. 

CIBERDEM researchers were invited to contribute to the 

DIAMAP Project by filling in its research questionnaire. 

This project, funded by the European Commission, 

aims to produce a «Road Map for Diabetes Research 

in Europe» that will include the inputs received from the 

network. 

A couple of proposals were presented with the assistance 

of this research support activity (Marie Curie 

Industry-Academia Partnerships and Pathways (IAPP) – 

FP7 which focus on researchers’ mobility through intersectorial 

exchanges and European Science Foundation - 

Research Conferences). 

CIBERDEM also started working together with 

the Spanish representatives in the European 

Commission with the aim of contributing scientifically, 

with the support of the Principle Investigators 

of the network, to the definition of European health 

priorities for 2011. 


There is much work remaining to be done for CIBERDEM 

to reach its projected level of participation in national 

and international research projects. CIBERDEM’s profile 

should become more visible in the international scientific 

community over the coming years. 

Thus, the challenges that lie ahead are: 

To increase collaborations between CIBERDEM and international 

partners in order to increase our participation 

in this kind of programme. 

To obtain funding for CIBERDEM research resulting 

from participation in national, European and other international 

calls. ■ 

18 CibeRdem

Training programme 

Introduction 

The training of research staff was envisaged right 

from the start of CIBERDEM and has been at the 

very centre of strategic action plan design ever since, 

especially the training of predoctoral staff and specialists 

with tenure. With the idea of developing a 

training plan, overseeing its work and guaranteeing 

its smooth running, CIBERDEM appointed a training 

committee made up of: President Antonio Zorzano 

Committee members Ramon Gomis, Angel Nadal, 

Joan J Vendrell. 

The aim of the training programme is to encourage 

the acquisition and transfer of knowledge, both basic 

and clinical, among the research staff under training 

in the groups which make up CIBERDEM in order to 

achieve the general research objectives as defined, 

while making better use of the resources available. 

The training programme represents an investment in 

our younger staff and in the future of the consortium 

itself. 

Objectives 

To create and implement a research staff training programme 

aimed especially at predoctoral researchers 

which will help participants to consolidate their investigative 

career, improve their future prospects and bring 

added value to the groups to which they belong. 

To enhance the methodological, technical, communicative 

and organizational skills of the younger members 

of the research staff and improve their scientific capacity 

in general. 

To increase mobility, communication and the transfer of 

scientific knowledge between the groups which make 

up CIBERDEM in order to develop their scientific proficiency, 

both basic and clinical. 


Renewal of contracts for predoctoral research staff 

Objective: A commitment to support young researchers 

so that they can carry out their work in the field of 

diabetes in a group of excellence linked to CIBERDEM. 

In 2009 CIBERDEM renewed the contracts of predoctoral 

grant holders as shown in the following table: 

Name 

Activity 

M Carrasco The role of the blockage of type 1 

VEGF receptor (VEGFR1) in obtaining 

insulin from adult pancreatic stem cells. 

E Rubio 

L Cadavez 

V Moreno 

The role of adipose tissue and adipokines 

in the development of type 2 

diabetes. 

The role of BACE in the functioning of 

pancreatic islets. 

The role of IRS-2 in the regeneration of 

the endocrine pancreas. 

The organization of an annual training course in 

translational matters with special emphasis on 

clinical research, aimed at CIBERDEM’s predoctoral 

researchers 

Objective: Regular ongoing training for predoctoral 

researchers (employees or associates) covering subjects 

of translational interest given by experienced 

CIBERDEM specialists or outside speakers. 

In 2009 CIBERDEM organized the following training 

course: 

Title An introduction to biomedical research in the field 

of diabetes 

Date 25-26 October, 2009 

Venue Arnes (Tarragona) 

Hours of classes 10 hours of classes, divided into two 

sessions: 

a. Fundamental clinical concepts in diabetes (5 papers 

of 1 hour each) 

b. An integral methodological approach to diabetes and 

associated comorbidities from a clinical perspective (5 

papers of 1 hour each) 

Participants 25 CIBERDEM junior researchers. 

Evaluation of the course 4,16 out of 5 

Training periods 

Objective: For junior and senior researchers to spend 

short periods (a maximum of three months) in other 

laboratories to broaden their scientific knowledge in 

specific techniques, collaborate with other groups and 

develop joint experiments. 


19

Date Name Destination Description 

31/1-3/3 

2009 

B García 

Postdoctoral 

European Bioinformatics Institute, Hinxton, 

Cambridge, UK 

Continuing study of microarray analysis 

and proposals for research projects. 

25/1-1/2 


R Fernández 

Postdoctoral 

Laboratory of Experimental Medicine, Free 

University of Brussels, Belgium 

A study of the role of phosphatase 

PTP1B in ER stress apoptosis mechanisms 

in beta cells. 

2/2-5/2 


F Escrivá 

Associate 

researcher 

Laboratorio de Neuroendocrinología 

Experimental, Centro de Investigación 

Príncipe Felipe, Valencia, España / 

CIBERDEM 

Methodological and conceptual approach 

to the analysis of IRS-2 in SNC, pancreas 

and islets of Langerhans. 

25/2-27/2 


A García 

Technician 

Laboratorio de Diabetes, Dpto. Bioquímica 

y Biología Molecular II, Universidad 

Complutense, Madrid, España / CIBERDEM 

Preparatory surgery for euglycaemichyperinsulinaemic 

clamping in mice; also 

the clamping itself. 

25/2-27/2 


R Fernández 

Postdoctoral 

Laboratorio de Diabetes, Dpto. Bioquímica 

y Biología Molecular II, Universidad 

Complutense, Madrid, España / CIBERDEM 

Preparatory surgery for euglycaemichyperinsulinaemic 

clamping in mice; also 

the clamping itself. 

8/6-9/6 


A Orozco 

Technician 




CIBERDEM 

Techniques for the culture of hESC cells 

for implantation in the laboratory. 

8/6-9/6 


A Gómez 

Principal 

Investigator 




CIBERDEM 

Techniques for the culture of hESC cells 

for implantation in the laboratory. 

1/6-30/6 


C Zabena 

Research 

assistant 

Depto. Endocrinología, Hospital Ramón y 

Cajal, Madrid, España 

Training in proteomic technology. 

29/6-10/7 


B Ropero 

Associate 

researcher 

Laboratorio de Diabetes y Endocrinología 

Experimental, IDIBELL, Barcelona, España / 

CIBERDEM 

Immunohistochemistry techniques for application 

to the pancreas. 

In 2009 there were 9 such visits under the auspices of CIBERDEM. ■ 

20 CibeRdem

Outreach activities 

2nd Annual Meeting 

More than 130 CIBERDEM researchers and staff 

members met to attend the 2nd CIBERDEM Annual 

Meeting, held in Arnes (Terra Alta, Tarragona, Spain) 

on October 26, 27 and 28, 2009. This scientific meeting 

allowed CIBERDEM research groups to share 

information on methods and the results of research 

projects with one another by means of 59 posters 

and 40 oral communications divided into 7 different 

sessions. 

In addition to the scientific aspect of the meeting, the 

event included guided tours to the medieval villages 

of Calaceite and Valderrobres, a typical wine tasting 

in the region, a digital photograph competition, and 

a gala dinner for all participants. The meeting was 

received with great enthusiasm and members were 

able to interact with one another and prepare the way 

for future collaborations. 

To cater for all aspects of this annual event, in May 2009 

the following website was set up: 

www.annualmeeting.ciberdem.org 

2nd Public Awareness Event 

The 2nd CIBERDEM Public Awareness Event 

«Investiga la diabetes» was held at the Science 

Museum in Barcelona, CosmoCaixa, on November 7, 

2009. The programme included exhibitions and interactive 

activities with the aim of showing the general public 

the latest advances in diabetes research. 

More than 350 people attended the event and took part 

in the different activities, including the lecture given by 

Dr Bernat Soria, researcher and ex-health minister, on 

the research being done in diabetes. Also, researchers 

and members of CIBERDEM participated in the creation 

and development of scientific workshops which 

opened up the world of science to all who attended. 

The event was also fortunate enough to have the collaboration 

of the Fundació Alícia, which conducted a 

workshop on research in the kitchen. 

2nd AnnuAl meeting 

CIBERDEM 

Arnes, October 26-28, 2009 

ABSTRACT BOOK 


Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders 

Abstract book cover of the 2nd Annual Meeting. 

investiga la diabetes’09 

CIBERDEM 


Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders 

Entrada gratuita previa inscripción 

Información y reservas: 

www.jornada.ciberdem.org 

Poster of the 2nd Public Awareness Event. 

Jornada de divulgación científica CibeRdeM 

Sábado 7 de noviembre de 2009 

10:30 a 15:00 horas 

CosmoCaixa Barcelona 


21

Dr Ramon Gomis, CIBERDEM Scientific Director, and 

Dr Anna Novials, CIBERDEM Principal Investigator, 

acted as moderators for the event. 

Newsletter 

On January 28, 2009, the first issue of «Tablón de anuncios 

CIBERDEM» (CIBERDEM noticeboard) came out. 

This provides CIBERDEM researchers with a valuable 

means of exchanging information and knowledge, but it 

is also available to any individual or institution wishing to 

receive it. This monthly newsletter has information on job 

offers and requests, calls, courses, publications and other 

news sent in by members of the CIBERDEM community. 

The «Tablón» is proving to be of great interest to everyone 

who receives it in their e-mail every month. Ample 

proof of this is provided by the increase in activity on 

the noticeboards and the fact that more and more people 

are receiving it; the mailing list currently stands at 

over 450 people. 

A month after each issue of the «Tablón», statistics are 

compiled in order to monitor its progress and analyse, 

for example, which subjects have been of most interest 

to readers so that future content may be tailored to users’ 

needs and preferences. The statistics are obtained 

from Mail Chimp, a newsletter management tool which 

has a database of 570 million e-mails on which to base 

its calculations. 


CIBERDEM plans to continue its outreach activities 

in the future with the hope of reaching a wider audience 

and increasing knowledge transfer and social 

impact. 

It is currently planning its 3rd Annual Meeting and 

a Public Awareness Event for 2010, anticipating 

higher levels of participation and more intense interaction 

with the diabetic community. In addition, 

CIBERDEM has already begun to place a renewed 

focus on internal exchanges between its research 

groups and on the promotion of collaborations specifically 

involving projects financed by international 

institutions. CIBERDEM hopes to meet the challenge 

of adapting its outreach activities to its changing 

needs and directions of growth. 

Also, with the aim of establishing efficient management 

channels, CIBERDEM will put in place a management 

intranet to facilitate access to all information 

and documentation concerning the consortium’s administrative 

procedures. 

Finally, by way of a scientific strategy, CIBERDEM 

intends to launch a fundraising campaign in order to 

obtain financing for research from individuals or companies. 

As part of this strategy, experts on the subject 

will disseminate up-to-date knowledge by giving 

lectures and talks on the current state of diabetes 

research. ■ 

600 

500 

Number of users who received newsletter 

Number of users who consulted newsletter 

Number of times newsletter was consulted 

400 

300 

200 

100 

0 

ia del sector "Medical and Healthcare". 

e emails para realizar sus c‡ lculos. 

Statistics of «Tablón de anuncios CIBERDEM», numbers 1-13. 

22 CibeRdem

Facts and figures

CIBERDEM members 

Basque Country: 1 group 

Community of Castile and Leon: 1 group 

Catalonia: 15 groups 

Community of Madrid: 10 groups 

Andalusia: 2 groups 

Valencian Community: 3 groups 

CIBERDEM groups (32) as of 31/12/2009, distributed among 6 Autonomous Communities of Spain. 

Area 1 

19% 

Area 2 

35% 

Area 3 

46% 

CIBERDEM members (437) as of 31/12/2009 by research area. 


25

200 

177 

Associates 

Employees 

150 

100 

103 

50 

46 

37 

15 17 

6 

27 

9 

0 

Doctorate 

Bachelor's degree 

(4 year) 


(3 year) 

Vocational degree 


CIBERDEM members (437) as of 31/12/2009 by professional category. 

Men 

24% 

50 

44 

40 

Permanent 

Temporary 

Women 

76% 

30 

20 

10 

17 

20 

13 

16 

11 

9 

2 

4 

0 

Doctorate 


(4 year) 


(3 year) 

Vocational degree 


CIBERDEM employees on staff (136) as of 31/12/2009 by professional category, type of contract and gender. 

26 CibeRdem

Scientific results 

Articles published by CIBERDEM groups Totals Percentage 

Total number of articles 105 

Total Impact Factor achieved 534,90 

Average Impact Factor 5,10 

Joint publications involving 2 or more CIBERDEM groups 10 9% 

Scientific articles citing CIBERDEM affiliation 80 76% 

Scientific articles in collaboration with other CIBERs 23 21% 

2009 Scientific publications. 

1st quartile 62% 

Other 10% 

2nd quartile 28% 

Percentage of publications by quartile of subject areas. 

250 

200 

IF=229,90 

IF=219,05 

150 

100 

IF=85,95 

50 

0 

Area 1 

Area 2 

Area 3 

Number of publications and Impact Factor by CIBERDEM areas: Area 1. Insulin signalling and resistance. Role in the onset of diabetes. 

/ Area 2. Dyslipidaemia, metabolic syndrome and microvascular complications of diabetes. / Area 3. Islet dysfunction, destruction 

and regeneration. Autoimmunity. Impact on the pathogenesis of diabetes. 


27

Autonomous Communities of Spain 18% 

National Projects from 

Spanish Ministries 

51% 

Private Institutions 20% 

European Comission 10% 

International Projects (NIH, NSF) 1% 

2009 Research projects and studies in progress (funding received by the institutions comprising CIBERDEM). 

Other International Research Groups 25% 

Other Spanish 

Research Groups 

50% IntraCIBER 8% 

InterCIBER 17% 

2009 Research collaborations. 

28 CibeRdem

Financial highlights 

ISCIII grants 

(CIBER programme) 

9.228.380,00 € 

Other revenue 

71.156,25 € 

2009 Total revenue obtained by funding entities. 6.853.544,51Û were the total resources applied during the year (74% of the total revenue). 

CIBERDEM Biobank 7% 

Metabolomics Platform 1% 

di@bet.es Study 7% 

Operating expenses 

49% 

Scientific equipment 15% 

Scientific platform support 4% 

Training programme 1% 

CIBERDEM research projects 16% 

2009 Expenses and assets by research initiative. 


29

Research


CIBERDEM projects and di@bet.es Study. 

Area 1 

Insulin signalling and resistance. Role in the onset of diabetes. 

Area 2 

Dyslipidaemia, metabolic syndrome and microvascular complications of diabetes. 

Area 3 

Islet dysfunction, destruction and regeneration. Autoimmunity. Impact on the pathogenesis of diabetes. 


31



di@bet.es Study


Introduction 

CIBERDEM seeks to achieve scientific excellence in 

research and encourage bench-to-bed as well as bedto-bench 

transition (see figures 1 and 2). In order to 

achieve these goals it promotes collaboration between 

basic and clinical research groups to prioritize translational 

research in the network. To this end, 14 initiatives 

based mainly on diabetes and its complications 

planned to last a year and a half have been instituted. 

CIBERDEM forges synergies between its members 

and launches initiatives that can offer an attractive opportunity 

to build up collaborations with other centres 

outside the consortium, whether national or international, 

because these projects can be seen as a pool of scientific 

knowledge that involve several Spanish research 

groups of excellence in diabetes at the same time. 


In 2010 we plan to continue the implementation of the 

projects with the aim of obtaining further results and 

applying for additional funding if possible. 

Collaboration between the research groups in this kind 

Clinical research groups Basic research groups 

of initiative will strengthen the participation of our members 

in future actions. 

STEMOB 

3 5 

MODIAB 1 3 

The 14 LOWHDL CIBERDEM 2 projects 3will increase our competitiveness 

and boost the significance of the network 

IODURE 1 4 

INGENFRED 

3 1 

within ENDODIAB the scientific 2 community 1 as well as bringing more 

DOTUM 1 2 

opportunities for competing for funding. 

DIASOBS 

CHILDBODYFAT 

4 1 

2 1 

Objectives 

To develop scientific actions focused on diabetes and 

its metabolic disorders with a high impact on research. 

To improve collaborations among CIBERDEM researchers, 

mainly among clinical and basic research 

groups (with a minimum participation of three research 

groups at the same time). 

To forge alliances between CIBERDEM researchers 

through joint work on the design and implementation 

of the projects. 

To demonstrate the competitiveness of CIBERDEM 

researchers and the innovation of their collaborative 

projects. 

To establish initiatives that a single CIBERDEM research 

group can not embark upon alone. 


During 2009 the call was opened, closed, evaluated 

and resolved. The Scientific Director and the 

Management Office followed the implementation of the 

14 CIBERDEM projects both scientifically and managerially 

from their inception in March. 

All the coordinators were invited to present their initiatives 

to the other CIBERDEM members at a meeting 

at the Parc Científic de Barcelona focusing on the 

activities carried out to date and the future challenges 

planned until the end of these activities. 

NEURONET-DIAB 

METADIAB 

IREVAS 

GIDIPRED 

ANTIBETACELL 

Basic research groups 

Clinical research groups 

2 1 

1 2 

2 1 

1 2 

2 1 

Figure 1. CIBERDEM bench to bed projects (NEURONET-DIAB, 

METADIAB, IREVAS, GIDIPRED, ANTIBECELL) showing the 

number of research groups participating in each project (in green 

the groups with a basic profile, in red those with a clinical profile). 

STEMOB 

MODIAB 

LOWHDL 

IODURE 

INGENFRED 

ENDODIAB 

DOTUM 

DIASOBS 

CHILDBODYFAT 


3 5 

1 3 

2 3 

1 4 

3 1 

2 1 

1 2 

4 1 

2 1 

Basic research groups 

Figure 2. CIBERDEM bed to bench projects (STEMOB, MODIAB, 

LOWHDL, IODURE, INGENFRED, ENDODIAB, DOTUM, 

DIASOBS, CHILDBODYFAT) showing the number of research 

groups participating in each project (in red the groups with a clinical 

profile, in green those Basic with research a basic groupsprofile). 


NEURONET-DIAB 

METADIAB 

IREVAS 

GIDIPRED 

ANTIBETACELL 

2 1 

1 2 

2 1 

1 2 


2 1 

33

The 14 projects 

The influence of insulin resistance states and their 

compensatory mechanisms by endocrine pancreas 

on endothelial/vascular damage. IREVAS 

Inflammation associated with obesity and type 2 diabetes 

mellitus, with insulin resistance as a common 

pathophysiological feature, produces qualitative and 

quantitative changes in the sub-endothelium. Thus, the 

objective of this study is to investigate the contribution 

of insulin resistance to endothelial/vascular damage, 

with or without the added complications of obesity. 

Groups: Manuel Benito, Deborah Burks, Ramon Gomis 

Project coordinator: Manuel Benito 

Identification of neurodegenerative mechanisms 

that promote the development of diabetic retinopathy: 

the role of insulin signalling and apoptosis. 

NEURONET-DIAB 

The molecular mechanisms which mediate the development 

of diabetic retinopathy (DR) remain unknown. 

Insulin and IGF-I signalling play important roles in the 

development and survival of retinal cells. Our hypothesis 

is that resistance to insulin/IGF-I in the retina disables 

the molecular mechanisms which protect retinal 

cells against stress and apoptosis, thereby triggering 

neurodegeneration and DR. The results will provide a 

rational basis for developing novel strategies to detect, 

prevent and treat DR in its earliest stages. 

Groups: Deborah Burks, Ángela Martínez Valverde, 

Rafael Simó 

Project coordinator: Deborah Burks 

Cooperative population and database studies for 

genetic association analysis in T2DM and related 

traits. INGENFRED 

Type 2 diabetes mellitus (T2DM) is a complex disease 

resulting from the interaction of environmental 

and genetic factors. The genetics of several functional 

systems in T2DM have not been dissected. The project 

aims to develop genetic T2DM studies, integrating 

different populations and databases, considering the 

interaction between genetic and environmental factors 

with the aim of developing future projects that will ultimately 

lead to clinical applications. 

Groups: Rafael Carmena, Francisco Blanco, Manuel 

Serrano Ríos, Federico Soriguer 

Project coordinator: Francisco Javier Chaves 

Clinical, genetic and functional characterization of 

monogenic diabetes: from the bench to the bedside. 

MODIAB 

Monogenic diabetes (MD) accounts for 1-2% of diabetes 

cases and is often misdiagnosed. Knowledge of the 

genetic aetiology of diabetes enables better treatment, 

prediction, disease progression, screening of relatives 

and genetic counselling. The project aims to determine 

aspects such as new genetic causes of MD, novel 

functional information for pancreatic beta cells and the 

importance of new regulatory sequences through the 

discovery of mutations in known genes. 

Groups: Luis Castaño, Enrique Blázquez, Jorge Ferrer, 

Mario Vallejo 

Project coordinator: Luis Castaño 

Diabetes and obesity treatment by tungstate: metabolic 

and molecular targets. DOTUM 

The plastic capacity of the pancreas to adapt to the 

metabolic necessities of the organism plays a key role 

in type 2 diabetes. This project aims to unravel the 

mechanisms controlling beta-cell plasticity; to dissect 

and determine the key players in the processes that 

adjust functional beta-cell mass; and to identify the role 

that peripheral tissues and the central nervous system 

play in plasticity control. Another goal is to work towards 

new therapeutic strategies through the analysis 

of several procedures such as the study of phosphatase 

inhibitors, for example, sodium tungstate. 

Groups: Ramon Gomis, Xavier Correig, Joan J Guinovart 

Project coordinator: Ramon Gomis 

Determinants of insulin resistance and glucose 

tolerance disorders (including diabetes) in severe 

obesity and their changes after bariatric surgeryinduced 

weight loss. DIASOBS 

Obese patients submitted to bariatric surgery present 

a marked weight loss that frequently normalizes abnormalities 

in glucose tolerance because obesity is the 

major risk factor for this kind of disorder. This project 

focuses on the identification of risk factors for insulin 

resistance, abnormal glucose tolerance and diabetes in 

severely obese patients, as well as on the identification 

of the determinants of the resolution of these disorders 

following the marked and sustained weight loss usually 

attained after bariatric surgery. 

Groups: Héctor F Escobar Morreale, Xavier Correig, 

Eduard Montanya, Rafael Simó, Joan J Vendrell 

Project coordinator: Héctor F Escobar Morreale 

Glycogen-induced dysfunctions in the pancreas 

and retina and their involvement in the ethiogenesis 

of diabetes mellitus. GIDIPRED 

The project is based on the idea that, contrary to the 

34 CibeRdem

general belief that supported glycogen being beneficial 

for cells, the deposition of glycogen may be deleterious 

for certain cell types. The aim is to study the alterations 

induced by this abnormal accumulation in pancreatic 

beta cells, neurons, and retinal cells. The working hypothesis 

is that the accumulation of this polysaccharide 

in these cell types contributes to the induction of apoptosis 

and therefore the pathological consequences associated 

with diabetes mellitus, namely reduced insulin 

secretion and retinopathy. 

Groups: Joan J Guinovart, Ramon Gomis, Rafael Simó 

Project coordinator: Joan J Guinovart 

Body fat amount and distribution in childhood 

determines predisposition to type 2 diabetes. 

CHILDBODYFAT 

Treatment with insulin sensitizing agents in SGAcatchup 

girls (girls born small for gestational age 

who show spontaneous catchup weight during childhood) 

improves insulin resistance, body fat excess and 

the adipokine pattern. The project aims to determine 

whether metformin can also revert these abnormalities 

in boys and in younger SGA children and whether it 

may directly influence specific lipolytic molecules or target 

the transcription factors involved in their expression. 

Groups: Lourdes Ibáñez, Xavier Correig, Lluís Masana 

Project coordinator: Lourdes Ibáñez 

The production of monoclonal antibodies which 

selectively react with cell surface molecules on human 

pancreatic beta cells. ANTIBECELL 

So far, it has not been possible to obtain an antibody 

that recognizes human beta cells, although the identification 

of these pancreatic cells in vitro and in vivo 

is highly desired. In this project we propose a novel 

immunization strategy making it possible to obtain immune 

response against antigens expressed poorly and 

to search for antibodies against receptors on the cell 

surface of pancreatic beta cells. The objective achievement 

opens new perspectives for studies in regeneration, 

development and cell therapy using islets. 

Groups: Franz Martín, Eduard Montanya, Angel Nadal 

Project coordinator: Juan Tejedo 

Characterization of low HDL syndrome in type 2 

diabetes. LOWHDL 

The macrovascular risk in type 2 diabetes mellitus patients, 

after receiving proper LDL-lowering therapy, is 

inappropriately high. This is partly attributed to the low 

HDL levels. Moreover, some drugs which raise HDL 

levels have failed to reduce the cardiovascular risk. 

Thus, LOWHDL mainly aims to characterize the HDL 

subclasses in T2DM patients both quantitatively and 

qualitatively and to study the impact of HDL increasing 

drugs on HDL qualitative changes. 

Groups: Lluís Masana, Francisco Blanco, Rafael 

Carmena, Xavier Correig, Manuel Vázquez-Carrera 

Project coordinator: Lluís Masana 

Comparative metabolomic analysis for the detection 

of biomarkers in diabetes. METADIAB 

In METADIAB, metabolomics is used to determine, 

thanks to the information provided by the endogenous 

metabolite profile, which metabolites are altered in diabetes. 

The changes that we aim to study are the consequences 

produced by high concentrations of glucose 

and lipids (glucolipotoxicity) in the islet pancreatic metabolome. 

Another aspect in which we are interested is 

the evaluation of the metabolomic effects induced by 

physical exercise in both type 1 and 2 diabetes mellitus. 

As a result, we will improve our knowledge in these 

situations and discover candidate biomarkers of the 

disease. 

Groups: Xavier Correig, Ramon Gomis, Anna Novials 

Project coordinator: Xavier Correig 

Mechanisms of endothelial dysfunction in diabetes: 

the role of amylin and circulating endothelial 

cells. ENDODIAB 

The main aetiology for death and for a high percentage 

of morbidity in patients with diabetes is vascular 

disease. Thus, this project aims to investigate circulating 

endothelial cells (CECs) as markers of endothelial 

dysfunction in diabetic patients; to determine the role 

of amylin in endothelial function; and to investigate the 

presence of preclinical atherosclerosis by assessing 

endothelial function in patients with type 1 diabetes 

mellitus, type 2 diabetes mellitus and obesity. 

Groups: Anna Novials, Ramon Gomis, María Luisa 

Villanueva-Peñacarrillo 

Project coordinator: Anna Novials 

The impact of overnutrition, diabetes-obesity and 

undernutrition on the regulation of energy homeostasis 

in the central nervous system. From animal 

models to humans. IODURE 

Increasing evidence suggests that the central nervous 

system plays a crucial role in regulating energy homeostasis 

through crosstalk with adipose tissue and the 

endocrine pancreas. The objective of the project is to 

investigate how the brain reacts to metabolic challenges 

associated with overnutrition, diabetes-obesity and 


35

undernutrition. It is expected that novel mechanisms responsible 

for the dysregulation of energy homeostasis 

which lead to obesity and diabetes will be identified. 

Groups: Manuel Serrano Ríos, Carmen Álvarez, 

Enrique Blázquez, Deborah Burks, Mario Vallejo 

Project coordinator: Manuel Serrano Ríos 

Adult adipose tissue-derived progenitor cells: the 

influence of the clinical phenotype and adipose depot 

origin in their biological properties. STEMOB 

The objective of this project is to test for differential 

behaviour in adult pre-adipocytes and adipocytes derived 

from adipose tissue mesenchymal stem cells (ad- 

MSC) obtained from lean and obese subjects and also 

to characterize adipose derived cells from a molecular 

and lipidomic perspective. The expected result is the 

identification of the differences in adMSC (from subcutaneous 

and visceral depots) that exist between lean 

and obese subjects. 

Groups: Joan J Vendrell, Jesús Balsinde, Anna Maria 

Gómez Foix, Margarita Lorenzo, Eduard Montanya, 

Rafael Simó, Manuel Vázquez-Carrera, Antonio 

Zorzano 

Project coordinator: Joan J Vendrell ■ 

36 CibeRdem

di@bet.es Study 

Introduction 

Attempts to halt the growing presence of diabetes in 

Spanish society, a cause of concern for both public 

and private healthcare systems, require reliable and 

accurate data on the incidence of diabetes in different 

groups within the Spanish population. di@bet.es, a joint 

initiative of the Spanish Diabetes Federation (FED), the 

Spanish Diabetes Society (SED) and CIBERDEM, was 

born with the goal of providing improved knowledge of 

the epidemiology of diabetes in Spain. 

CIBERDEM, primary funding organization of di@bet.es, 

believes firmly in the importance of the epidemiological information 

that the study will provide as a point of reference 

for measuring the success of its programmes. The results of 

this study will assist CIBERDEM groups in focusing their research 

on relevant pursuits and will allow public and private 

institutions to formulate more efficient and effective strategies 

for diabetes prevention, diagnosis, treatment and research. 

Objectives 

To determine the overall incidence (known and unknown) 

of type 2 diabetes mellitus in a representative 

sample of the Spanish population. 

To determine the relationship between the incidence of 

type 2 diabetes mellitus and the nutritional habits and 

physical activity of the individuals within the sample, as 

well as relevant information regarding their demographic 

and genetic characteristics. 

To provide a scientific tool for assessing institutional 

health strategies. 

To determine the incidence of impaired fasting glucose 

and impaired glucose tolerance, insulin-resistance, hypertension, 

dyslipidaemia, obesity, and metabolic syndrome 

in a representative sample of the Spanish population. 

To determine the relationship between the incidence of 

these disorders and the nutritional habits and physical 

activity of the individuals within the sample. 

To provide a collection of human serum samples for 

carrying out studies on the analysis of gene-environment 

interaction in the pathogenesis of diabetes. 


Direction Federico Soriguer (Hospital Carlos Haya- 

IMABIS, Málaga, and CIBERDEM). 

Field work regions. 

Central region 

Northern region 

Southern region 

Northeastern region 

Eastern region 

Coordination Gemma Pascual (CIBERDEM Management 

Office) and Gemma Rojo (Hospital Carlos Haya- 

IMABIS, Málaga, and CIBERDEM). 

Northern region Field work coordination and 

CIBERDEM Management: Luis Castaño (Hospital de 

Cruces, Bilbao, and CIBERDEM). Field work: Alicia 

Cobo, Ana María Megido. 

Northeastern region Field work coordination: Albert 

Goday (Hospital del Mar de Barcelona). CIBERDEM 

Management: Ramon Gomis (Hospital Clínic de 

Barcelona, IDIBAPS, and CIBERDEM). Field work: 

Alba Arocas, Laura Esquius, Rosario Suarep, María 

Dolores Zomeño. 

Eastern region Field work coordination: Miguel 

Catalá (Hospital Clínico de Valencia and CIBERDEM). 

CIBERDEM Management: Rafael Carmena (Hospital 

Clínico de Valencia and CIBERDEM). Field work: Clara 

Bixquert, Nieves Brito. 

Central region Field work coordination: Alfonso 

Calle (Hospital San Carlos de Madrid). CIBERDEM 

Management: Manuel Serrano Ríos (Hospital San 

Carlos de Madrid and CIBERDEM). Field work: Isabel 

Alonso, Enrique Mañas. 

Southern region Field work coordination: Gemma 

Rojo (Hospital Carlos Haya-IMABIS, Málaga, and 

CIBERDEM). CIBERDEM Management: Federico 


37

Soriguer (Hospital Carlos Haya-IMABIS, Málaga, and 

CIBERDEM). Field work: Rocío Badía, Isabel Guillén. 

Other Steering Committee members Alfonso López 

Alba (Hospital Universitario de Canarias, Tenerife), 

Elena Bordiu (Hospital San Carlos de Madrid), Roser 

Casamitjana (Hospital Clínic de Barcelona, IDIBAPS, 

and CIBERDEM), Conxa Castell (Consejo Asesor sobre 

la Diabetes. Dirección General de Salud Pública, 

Generalitat de Catalunya, Barcelona), Elias Delgado 

(Hospital General de Asturias), Edelmiro Menéndez 

(Hospital Universitario Central de Astúrias), Josep Franch 

(Centre d’Atenció Primària Raval Sud, Barcelona), José A 

Vázquez (Hospital de Cruces, Bilbao), Sonia Gaztambide 

(Hospital de Cruces, Bilbao, and CIBERDEM), Juan 

Girbés (Hospital Arnau de Vilanova de Valencia), María 

Teresa Martínez-Larrad (Hospital San Carlos de Madrid 

and CIBERDEM), Emilio Ortega (Hospital Clínic de 

Barcelona, IDIBAPS, and CIBERDEM), Inmaculada 

Mora (Hospital Universitario de Canarias, Tenerife), 

Sergio Valdés (Hospital Carlos Haya-IMABIS, Málaga, 

and CIBERDEM), and, Joan J Vendrell (Hospital Joan 

XXIII de Tarragona and CIBERDEM). 


di@bet.es still has nearly a year of hard work ahead of 

it in order to reach its established objectives: 

Field work in four of the regions of the study will continue 

during the next year in order to obtain a total of 

approximately 5,000 samples by the end of di@bet.es. 

Statistical analysis will be performed with a view to presenting 

publicly the final results on the incidence of diabetes 

in different groups within the Spanish population. 

The information obtained will be made available to the 

Spanish health authorities to allow them to dedicate the 

appropriate resources to the treatment of diabetic patients 

in the public healthcare system. 

The sample collection in the CIBERDEM Biobank will 

be available to allow the scientific community to develop 

new scientific projects that will improve knowledge 

of the epidemiology of the Spanish population. ■ 


During 2009 after the completion of the initial phase of 

di@bet.es: 

The remaining field teams were contracted and all began 

work covering the whole of the country. 

The six field work teams corresponding to the five geographical 

regions (one of the areas is reinforced with 

an extra team), carried out their tasks collecting serum 

samples from individuals, aged from 18 to 89, selected 

to participate in the study. Samples from more than 

3,000 subjects were compiled during the course of the 

year together with the corresponding demographic, 

social and clinical data including relevant information 

such as the lifestyle factors. 

Work in one of the five geographical regions was 

completed. 

Non-concluding results from the first phase of di@ 

bet.es were obtained, studied and discussed by the 

Steering Committee. 

It was decided that the sample collection resulting from 

the di@bet.es Study should be stored in the CIBERDEM 

Biobank (technological platform) with the aim of providing 

the scientific community with this valuable material 

that could in the future be a source of potential relevant 

scientific studies with high impact on the epidemiology 

of the Spanish population. 

38 CibeRdem

Area 1 

Insulin signalling and resistance 

Role in the onset of diabetes

In 2009, we welcomed a new lab led by María Luisa Villanueva-Peñacarrillo devoted to the study of the role of 

incretins in the regulation of glucose metabolism. 

Our main concern was to study metabolic alterations and complications such as inflammation or vascular damage 

related to insulin resistance associated with type 2 diabetes and obesity. For this reason, we are identifying novel 

insulin resistance and type 2 diabetes susceptibility genes that may control metabolic homeostasis, nuclear gene 

expression and autophagy in insulin resistance. In addition, we are identifying new control mechanisms of glycogen 

metabolism in the liver and skeletal muscle and their alterations in diabetes mellitus and the consequences 

of altered glycogen deposition in several tissues in diabetes mellitus, including the characterization of novel 

compounds with an anti-diabetic action. We focused especially on the study of factors governing human muscle 

gene expression and also on fatty acid in muscle and the deleterious effect in high-fat-diet-induced diabetes. 

Furthermore, we are developing new cellular models in relation to major insulin target tissues such as brown 

adipocytes, hepatocytes and myocytes, beta cells and also vascular cells. In these cells, we knock out or knock 

down insulin resistance candidate genes to study the molecular mechanism of insulin resistance and sensitivity 

and the implication of some proinflammatory signals related to type 2 diabetes and obesity-induced diabetes. We 

are developing new mouse models of insulin resistance, type 2 diabetes and obesity. Finally, the metabolomic 

platform is developing the analysis and characterization of lipoprotein subclass analysis in serum samples. 

Among the achievements of 2009, we demonstrated that morbidly obese type 2 diabetic patients show a defect 

in the regulatory pathways that induce genes involved in mitochondrial biogenesis/function. We also showed 

that caveolin-1 plays a major role in the expression of insulin receptors and GLUT4 in adipocytes. In addition, 

differentiation of brown adipocytes evolves through different signalling pathways from white adipocytes, with 

AMPK-mTOR cross-talk. Turning to glycogen metabolism, we demonstrated the control role of the PP1 glycogenassociated 

regulatory subunit PPP1R6 on glycogen metabolism in cultured muscle cells. In addition, we deployed 

a high-sensitivity microarray platform to identify the differential transcriptome between human aneurally cultured 

myotubes and skeletal muscle tissue. As regards liver metabolism, we demonstrated that the absence of PTP1B 

in double mutant IRS-2 -/- /PTP1B -/- mice restored hepatic IR/IRS-1-mediated PI 3-kinase/Akt/FoxO1 signalling 

and the inhibition of gluconeogenic genes in response to insulin. Regarding modelling diabetes and obesity, 

we developed a new mouse model of diabetes, obesity, insulin resistance and vascular damage. Failure in the 

compensatory mechanism to insulin resistance aggravated vascular damage. Finally, we completed the settingup 

of the MS-based analytical platforms: GC-MS, HPLC-TOF and LC-MS/MS. 

Manuel Benito 

CIBERDEM Scientific Area Coordinator 


41

Diabetes and cardiovascular 

Facultad de Farmacia, Universidad Complutense de Madrid 

www.ucm.es/info/biomol2 

Principal Investigator Manuel Benito Associate researcher Óscar Escribano, Almudena Gómez, 

Carlos Guillén Postdoctoral fellow Beatriz Gozalbo PhD student Alberto Bartolomé, Natividad Moreno, 

Yolanda Otero Lab technician Silvia Fernández, Gema García Administrative staff Cristina Pérez 

Keywords 

Beta-cell signal transduction. Cytokines. Insulin sensitivity 

and resistance. Islet development. Macrovascular 

disease. 

State of the art 

Insulin resistance, among other physiopathological 

features, is the main gate to the progression to 

type 2 diabetes. Our group is mainly focused on the 

development of new mouse and cellular models for 

the study of insulin sensitivity or resistance. Indeed, 

vascular damage is often seen when patients are diagnosed 

with type 2 diabetes. Thus, we paid special 

attention to the generation of a new mouse model of 

insulin resistance and cardiovascular damage. In addition, 

we have developed new cellular models for the 

study of the molecular basis of insulin resistance in 

the vasculature. 

Main lines of research 

Inducible insulin receptor liver-specific knockout 

(iLIRKO): a mouse model for the study of insulin resistance, 

beta-cell hyperplasia and vascular dysfunction in 

response to insulin. 

Obese BATIRKO mice: a mouse model for the 

study of insulin resistance, compensatory mechanisms 

of insulin resistance, lipid mobilization, lipid 

accumulation, vascular markers of lesion and vascular 

lesion. 

The integration of insulin and glucose signalling in the 

activation of beta-cell proliferation. 

The generation of new cardiovascular and endothelial 

cells lacking IR. 

The role of IRA/IRB ratio in insulin action and inaction. 

Areas of expertise 

Insulin signalling. 

Insulin resistance. 

Compensatory mechanisms to insulin resistance. 

Brown fat thermogenesis. 

White fat adipogenesis and local inflammation. 

Endothelial dysfunction. 

Markers of vascular lesions. 

42 CibeRdem


We have developed a new inducible mouse model of 

hepatic insulin resistance (iLIRKO). Thus, we have 

been able to establish a cause and effect relationship 

between the level of insulin receptor (IR) deletion, the 

level of the beta-cell mass hyperplasia and the level of 

circulating insulin. In addition, we have demonstrated 

that liver factors such as IGF-1 induced because of the 

IR deletion in the liver are involved in the beta-cell hyperplasia 

observed in the pancreas, suggesting a liverpancreas 

endocrine axis. 


We want to address the issue of the role played by the 

compensatory mechanisms to insulin resistance induced 

in obese BATIRKO mice. Thus, a possible link 

between brown adipose tissue, insulin secretion by the 

islets, white adipose tissue insulin signalling and the 

expression of adipokines and cytokines and vascular 

damage will be studied. In addition, we will assess the 

attenuation of vascular lesions observed in apo E -/- 

mice within the genetic background of BATIRKO. 

Publications 

Original article 

Escribano O, Guillén C, Nevado C, Gómez-Hernández 

A, Kahn CR, Benito M. Beta-Cell hyperplasia induced 

by hepatic insulin resistance: role of a liver-pancreas 

endocrine axis through insulin receptor A isoform. 

Diabetes, 58, 820-828 (2009) 

Book chapter 

Lorenzo M, Benito M. «From Insulin Action to Hormonal 

Resistance. Old to Recent Molecular Mechanisms», in 

Type 2 Diabetes Mellitus. Elsevier, 105-129 (2009) 

Research networks and grants 

CIBERDEM project 


compensatory mechanisms by endocrine pancreas on 

endothelial/vascular damage 

IREVAS: 2009-2010 

Principal Investigators: Manuel Benito, Deborah Burks, 

Ramon Gomis 


National project 

Modelos animales y celulares de resistencia a la insulina: 

daño cardiovascular 

MICINN, SAF2008-00031: 2009-2011 

Principal Investigator: Manuel Benito 

Autonomous Community project 

Diabetes y cardiovascular (group 920384) 

CAM/UCM gr58/08: 2009-2010 

Principal Investigator: Manuel Benito 

Awards 

«FAES FARMA», Real Academia Nacional de Farmacia 

(2009) 

Awardees: A Bartolomé, C Guillén, M Benito ■ 

Isolation of beta islets. 


43

Metabolomics Platform 

Universitat Rovira i Virgili, Institut d’Investigació Sanitària Pere Virgili, Tarragona 

www.metabolomicsplatform.com 

Principal Investigator Xavier Correig Associate researcher Jesús 

Brezmes, Nicolau Cañellas Research assistant Miguel Ángel 

Rodríguez, Maria Vinaixa PhD student Roger Mallol, Sara Samino, 

Julia Sigles Lab technician Antoni Beltran 

Keywords 

Lipid metabolism. Lipids, lipoproteins. Metabolomics. 

Bioinformatics. 


Metabolomics is the newest «-omics» science 

employed together with genomics and proteomics 

towards the understanding of global systems biology. 

It is mainly aimed at profiling all the small 

molecule metabolites found within body fluid, 

a cell, tissue, organ or organism. In diabetes 

and metabolic-disease research, this technique 

would be put to the test by its ability/capacity to 

assess large human populations or investigate a 

range of different tissues in animal studies both 

rapidly and cheaply, usually by high throughput 

screening. 


We are currently dealing with the following research 

areas: 

Lipoprotein subclass analysis and the characterization 

of serum samples. 

The identification and quantification of a wide range of 

metabolites in cell culture lines and different bio-fluids. 

The development and study of advanced statistical, 

chemometric, multivariate and artificial intelligence algorithms 

which will allow large measurement datasets 

to be turned into useful clinical information. 

The development of data mining algorithms. 


The development of a metabolomics-based project is 

made up of several major operations that involve experimental 

design, sample handling, analytical measurements 

and data analysis. 

The platform provides expertise through all these operations 

which serve to enhance CIBERDEM’s research 

capabilities. 

The Metabolomics Platform facility is embedded in a 

strong bioinformatics environment that builds upon expertise 

in data management, multivariate data analysis 

and artificial intelligence. 

44 CibeRdem


An important achievement during 2009 has been the 

whole setting-up of the MS-based analytical platforms: 

GC-MS, HPLC-TOF and LC-MS/MS. This equipment, 

together with NMR technologies, provides the 

Metabolomics Platform with the most outstanding, 

state-of-the-art equipment in metabolomics. 

The main technologies developed were: NMR metabolite 

profiling from tissue extracts, cell cultures and 

secretomes; serum and urine fingerprinting by NMR; 

and serum lipoprotein subclass identification and 

quantification. 


The main goal of the platform is to consolidate this 

structure as a valuable tool to promote and support 

activities in the metabolomics field within CIBERDEM 

research groups, gradually becoming involved in most 

of their main research lines. 

The most important scientific challenge for the 

Metabolomics Platform is data mining from the different 

analytical platforms as well as with data from other 

«-omics» sciences (mainly genomics, transcriptomics 

and proteomics). 

Publications 


Rull A, Vinaixa M, Angel Rodríguez M, Beltrán R, Brezmes 

J, Cañellas N, Correig X, Joven J. Metabolic phenotyping 

of genetically modified mice: An NMR metabonomic approach. 

Biochimie, 91, 1053-1057 (2009) 



Body fat amount and distribution in childhood determines 

predisposition to type 2 diabetes 

CHILDBODYFAT: 2009-2010 

Principal Investigators: Lourdes Ibáñez, Xavier Correig, 

Lluís Masana 


Determinants of insulin resistance and glucose tolerance 

disorders, including diabetes, in severe obesity 

and their changes after bariatric surgery-induced 

weight loss 

DIASOBS: 2009-2010 

Principal Investigators: Héctor F Escobar Morreale, 

Xavier Correig, Eduard Montanya, Rafael Simó, Joan 

J Vendrell 



and molecular targets 

DOTUM: 2009-2010 

Principal Investigators: Ramon Gomis, Xavier Correig, 

Joan J Guinovart 



diabetes 

LOWHDL: 2009-2010 

Principal Investigators: Lluís Masana, Francisco 

Blanco, Rafael Carmena, Xavier Correig, Manuel 

Vázquez-Carrera 


HR-MAS spectra of pancreatic Islets. 

S-TOCSY correlation of a lipid extract with steatosis score. 


45

Comparative metabolomic analysis for the detection of 

biomarkers in diabetes 

METADIAB: 2009-2010 

Principal Investigators: Xavier Correig, Ramon Gomis, 

Anna Novials 



Neurodegeneración en la patogénesis de la retinopatía 

diabética incipiente. Estudio de los mecanismos implicados 

a través de un abordaje integrado de biología de 

sistemas 

Ministerio de Educación y Ciencia, SAF 2009-07408: 

2009-2011 

Principal Investigator: Rafael Simó 

Associate investigator: Miguel Ángel Rodríguez 

Dislipemia Aterógena de la Obesidad, Síndrome 

Metabólico y Diabetes tipo 2: Caracterización 

Metabólica y Mecanismos Patogénicos 

FIS, PI081409: 2008-2011 

Principal Investigator: Lluís Masana 

Associate investigator: Jesús Brezmes 

Caracterización bioquímica, metabólica y genética 

de la hipertrigliceridemia asociada a alto riesgo 

cardiovascular 

FIS, PI081579: 2008-2011 

Principal Investigator: Josep Ribalta 

Associate investigator: Nicolau Cañellas ■ 

46 CibeRdem

Mechanisms of control of glucose and 

fatty acid metabolism in skeletal muscle cells 

and metabolic impairment in atrophy 

Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona 

www.bq.ub.es 

Principal Investigator Anna Maria Gómez Foix Associate researcher Cèlia García Postdoctoral 

fellow Maria Guitart, Marta Montori PhD student Emma Mormeneo Lab manager Anna Orozco 

Keywords 

Carbohydrate metabolism. Insulin sensitivity and resistance. 

Lipid metabolism. 


Skeletal muscle tissue consumes glucose and fatty acids 

competitively and displays a high metabolic demand 

linked to contraction. Imbalances in the metabolism of 

skeletal muscle and/or impairment of its insulin sensitivity 

are pathogenic factors in type 2 diabetes. In type 

2 diabetes, skeletal muscle shows decreased fatty acid 

oxidative capacity and impaired switching from fatty 

acid to glucose oxidation in response to insulin. Skeletal 

muscle atrophy, due to disuse, denervation or aging is 

associated with a metabolic reductive phenotype and 

insulin resistance. There is little understanding of the 

mechanisms directing such phenotype adaptations. 


Mechanisms of control of skeletal muscle glycogen 

metabolism. 

Differential functionality of the protein phosphatase 1 

(PP1) glycogen-associated regulatory subunits present 

in human skeletal muscle (G M 

(PPP1R3A), PTG 

(PPP1R3C) and PPP1R6 (PPP1R3D)). 

Factors governing human muscle glycogen phosphorylase 

(PYGM) gene expression. 

Metabolic control role of the fatty acid transport protein 

1 (FATP1) in muscle and its deleterious effect in highfat-diet-induced 

diabetes. 

Phenotype of cultured myotubes derived from human 

skeletal muscle biopsies by the explant technique. 


Skeletal muscle glycogen metabolism. 

Metabolic control by membrane-bound fatty-acid-binding 

proteins. 

Transcriptomic and metabolic profile of primary cultured 

human skeletal muscle. 


We have described the control role of the PP1 


47

Graphical representation of differentially expressed genes involved in mitochondrial function in human cultured myotubes compared to 

skeletal muscle tissue and their molecular relationships. Genes are represented as nodes. Node colour indicates direction of change 

of gene expression (green downregulated, red upregulated); colour intensity shows magnitude of change. The lines in between genes 

represent known interactions. The pathway image was created using IPA software. 

glycogen-associated regulatory subunit PPP1R6 in glycogen 

metabolism in cultured muscle cells by means 

of adenovirus-mediated overexpression, in comparison 

with the PTG and G M 

subunits. 

We have shown that FATP1 is localized inside the mitochondria 

in cultured skeletal myotubes. This localization 

may explain the activation of the mitochondrial 

pyruvate dehydrogenase complex by FATP1, while palmitate 

counteracts this activation. 

We have shown that PYGM gene expression is stimulated 

by cAMP in cultured muscle cells and PGC1- 

alpha mediates this effect. 

We deployed a high-sensitivity microarray platform to 

identify the differential transcriptome between human 

aneurally cultured myotubes and skeletal muscle tissue. 

Cultured myotubes display reductive metabolic (mainly 

mitochondrial) metabolism, and muscle-system transcriptome, 

as observed in muscle atrophy, and activate tissueremodelling 

and senescence/apoptosis processes. 


Our immediate future objectives are: to unveil the mechanisms 

that confer glucose-sensitivity to the PP1 glycogen-associated 

regulatory subunits G M 

and PPP1R6; 

to define the metabolic control role of FATP1 in skeletal 

muscle in rats fed a standard or fat diet; and to test 

the capacity of PGC1-alpha, a key metabolic enhancer 

involved in protection against muscle atrophy, to adjust 

the phenotype of metabolically-impaired and atrophic 

human skeletal muscle cultures. 

Publications 


Guitart M, Andreu AL, García-Arumi E, Briones P, 

Quintana E, Gómez-Foix AM, García-Martínez C. 

FATP1 localizes to mitochondria and enhances pyruvate 

dehydrogenase activity in skeletal myotubes. 

Mitochondrion, 9, 266-272 (2009) 

Montori-Grau M, Minor R, Lerin C, Allard J, Garcia- 

Martinez C, de Cabo R, Gómez-Foix AM. Effects of 

aging and calorie restriction on rat skeletal muscle 

glycogen synthase and glycogen phosphorylase. Exp 

Gerontol, 44, 426-433 (2009) 

Sebastián D, Guitart M, García-Martínez C, Mauvezin 

C, Orellana-Gavaldà JM, Serra D, Gómez-Foix AM, 

Hegardt FG, Asins G. Novel role of FATP1 in mitochondrial 

fatty acid oxidation in skeletal muscle cells. J Lipid 

Res, 50, 1789-1799 (2009) 



Adult adipose tissue-derived progenitor cells: the influence 

of the clinical phenotype and adipose depot origin 

48 CibeRdem

in their biological properties 

STEMOB: 2009-2010 

Principal Investigators: Joan J Vendrell, Jesús Balsinde, 

Anna Maria Gómez Foix, Margarita Lorenzo, Eduard 

Montanya, Rafael Simó, Manuel Vázquez-Carrera, 

Antonio Zorzano 

Project coordinator: Joan J Vendrell 


Estudio del metabolismo muscular de la glucosa y sensibilidad 

a la insulina usando como modelo el cultivo de 

músculo humano no inervado. Relación con la diabetes 

tipo 2 asociada a la atrofia muscular 

MEC, SAF2006-07228: 2006-2009 

Principal Investigator: Anna Maria Gómez Foix 


Acreditació de Grup de Recerca de Catalunya 

Generalitat de Catalunya, 2009 SGR 10: 2009-2013 


Desenvolupament d’un dispositiu d’electroporació a 

plaques estàndard multipouet 

Centro de Innovación y Desarrollo Empresarial (CIDEM), 

Generalitat de Catalunya, VALTEC09-1-00061: 



Project coordinator: Ramon Bragós 

Ajut per la contractació de personal de suport a la 

recerca 

Generalitat de Catalunya, SGR00932: 2007-2010 


Project coordinators: AM Gómez Foix, A Boronat ■ 

Ad-GFP 

Ad-R6 

Ad-PTG 

Ad-G M 

Glycogen accumulation in skeletal muscle cells overexpressing 

PP1 glycogen-associated regulatory subunits. Electronic microscopy 

images of cultured human myotubes transduced with control 

adenovirus (Ad-GFP) or adenovirus encoding PPP1R6 (Ad-R6), 

PTG (Ad-PTG) or GM (Ad-GM). Arrows mark glycogen particles. 


49

Metabolic engineering and diabetes therapy 

Institut de Recerca Biomèdica, Barcelona 

www.irbbarcelona.org 

Principal Investigator Joan J Guinovart Associate researcher Joaquim Calbó, Jorge Domínguez, María 

del Mar García Postdoctoral fellow Daniel Cifuentes, Adelaida Díaz, Jordi Duran, Carlos Rodríguez, 

Florencia Tevy, David Vílchez, Delia Zafra Research assistant Anna Adrover PhD student Óscar Blanco, 

Mireia Díaz, Carles Martínez, Laura Nocito, Susana Ros, Isabel Sáez, Juan Felipe Slebe, Carlos Spichiger, 

Jordi Vallès Lab technician Lydie Babin, Emma Veza Administrative staff Carolina Sánchez 

Keywords 

Carbohydrate metabolism. Insulin sensitivity and resistance. 

Metabolic syndrome. Oral pharmacological 

agents. Retinopathy. 

neurodegenerative diseases. 

The identification of potential molecular targets that 

regulate glycogen metabolism and the characterization 

of novel compounds with anti-diabetic action. 


We are involved in the study of glycogen metabolism and 

its dysfunctions in diabetes mellitus and neurodegenerative 

diseases. New factors and processes that participate 

in the regulation of glycogen metabolism regulation 

are constantly being discovered. The alteration of one 

of these mechanisms may lead to serious pathologies 

such as diabetes mellitus and its complications. In addition, 

we have identified and are currently characterizing 

a new oral anti-diabetic and anti-obesity agent. 


Mechanisms of control of glucose storage in the liver 

and muscle and their alterations in diabetes mellitus. 

The consequences of altered glycogen deposition 

in various tissues in diabetes mellitus and in several 


The regulation of glycogen metabolism; the analysis of 

alterations in diabetes and Lafora disease. Schematically: 

the regulatory domains of glycogen synthase (GS); the 

physiological significance of GS translocation; the regulatory 

role of malin and laforin in glycogen metabolism; the 

alterations of glycogen metabolism in pathology; the study 

of anti-diabetic agents and their possible application; the 

identification of the molecular targets of sodium tungstate; 

the identification of new molecular targets for the design of 

the anti-diabetic and anti-obesity agent sodium tungstate. 


The identification of Serine-8 as the key phosphorylation 

site involved in the activation of liver glycogen synthase 

(LGS). 

50 CibeRdem

The increase of glycogen deposition and improvement 

of diabetic status through the adenoviral transduction 

of the non-phosphorylatable S8A mutant-LGS in primary 

cultured hepatocytes and in diabetic rats. 

The generation of transgenic animals to reproduce 

tissue-specific alterations in glycogen deposition and 

model diabetic complications and other pathologies. 

New structural insights into the molecular organization 

of GS. 

The definition of the action mechanism of sodium tungstate 

and the identification of novel putative therapeutic 

targets for the treatment of diabetes mellitus. 


To study whether abnormal glycogen accumulation 

is involved in the onset of diabetes mellitus and its 

complications. 

To study the effects of glycogen synthesis activation in 

the liver as a therapeutic approach for the treatment of 

diabetes mellitus. 

To gain insight into the dynamic processes affecting the 

glycogen molecule (synthesis, modification, signalling, 

degradation). 

To identify new drugs for the treatment of pathologies 

related to glycogen metabolism. 

Publications 


Reverter JL, Nadal J, Fernández-Novell JM, 

Ballester J, Ramió-Lluch L, Rivera MM, Elizalde J, 

Abengoechea S, Guinovart JJ, Rodríguez-Gil JE. 

Tyrosine phosphorylation of vitreous inflammatory 

and angiogenic peptides and proteins in diabetic retinopathy. 

Invest Ophthalmol Vis Sci, 50, 1378-1382 


Ros S, García-Rocha M, Domínguez J, Ferrer JC, 

Guinovart JJ. Control of liver glycogen synthase activity 

and intracellular distribution by phosphorylation. J Biol 

Chem, 284, 6370-6378 (2009) 









Glycogen-induced dysfunctions in the pancreas and 

retina and their involvement in the ethiogenesis of diabetes 

mellitus 

GIDIPRED: 2009-2010 

Principal Investigators: Joan J Guinovart, Ramon 

Gomis, Rafael Simó 



Estudio de un nuevo mecanismo de regulación del metabolismo 

del glucógeno. Análisis de las implicaciones 

patológicas de la acumulación anómala de polímeros 

de glucosa 

Ministerio de Ciencia e Innovación, BFU2008-00769: 


Principal Investigator: Joan J Guinovart 


Ayudas de apoyo a grupos de investigación 

Generalitat de Catalunya (AGAUR), SGR2009-1176: 



Ultrastructural image of glycogen deposits (electrodense dots) in 

the cytoplasm of rat hepatocytes. 

Private funds 

Mejora de la predicción traslacional de los ensayos de 

seguridad no clínica al hombre 


51

CDTI-Noscira (formerly Neuropharma), MELLIUS 

(CENIT): 2007-2010 


Awards 

«Premi Prat de la Riba», Institut d’Estudis Catalans (2009) 

Awardee: Joan J Guinovart ■ 

52 CibeRdem

Obesity, inflammation and insulin resistance 

Departamento de Bioquímica, Facultad de Farmacia, Universidad Complutense de Madrid 

www.ucm.es/info/insulin 

Principal Investigator Margarita Lorenzo (1958-2010) Associate researcher Sonia Fernández 

Postdoctoral fellow María Alonso, Iria Nieto Research assistant Elena González PhD student Lucía 

García, Ana Vázquez, Rocío Vila Lab technician Loa Muñoz 

Keywords 

Cytokines. Exercise. Glucose transport. Insulin sensitivity 

and resistance. Lipid metabolism. 


Insulin resistance is an important contributor to the 

pathogenesis of type 2 diabetes and obesity is a risk 

factor for its development. It has been demonstrated 

that these obesity-related metabolic disorders are associated 

with a state of chronic low-intensity inflammation. 

It has been suggested that several mediators released 

from adipocytes and macrophages, such as the 

pro-inflammatory cytokines TNF-alpha and IL-6, may 

impair insulin action in peripheral tissues, including fat 

and skeletal muscle. 


Insulin resistance induced by cytokines such as TNFalpha, 

IL-6, IL-1 beta or leptin and hyperisulinaemia in 

murine and human muscle and adipose cells. Studies 

on mice are also being performed. 

The study of glucose homeostasis and insulin sensitivity 

in GRK-2 heterozygous mice. 

The contribution of PTP1B to insulin action on glycogen 

metabolism in myocytes: PTP1B as a target for the prevention 

and treatment of insulin resistance. 

Pharmacological approaches, such as treatment 

with PPAR and LXR agonists which overcome insulin 

resistance. 


Primary and cell-line phenotyping. 

Cell-line immortalization from mouse models of insulin 

sensitivity and resistance. 

Insulin signalling and insulin action. 

Glucose and lipid metabolism. 

Transcription factors and nuclear receptors. 


Our major discoveries have been as follows: TNF-alpha 

induces insulin resistance on glucose uptake in human 

visceral but not subcutaneous adipocytes, suggesting 


53

Cross-talk between AMPK and mTOR-p70S6K1 signalling pathways occurs during brown adipocyte differentiation. Activation of 

mTOR-p70S6K1 signalling pathway in the early proliferative step is an absolute requirement to reach a fully brown differentiated phenotype 

and might be related to cell growth and proliferation processes. On the other hand, further activation of AMPK is also required, 

and may be involved in the inhibition of mTOR-p70S6K1 signalling cascade later in the differentiation process, via TSC2 activation, 

as well as in the expression of thermogenic markers. 

depot-specific effects of TNF-alpha on glucose uptake; 

the activation of JNK1/2 appears to be involved 

in serine phosphorylation of IRS-1 and subsequently 

insulin resistance on glucose uptake, a state that can 

be reversed by LXR agonists; the differentiation of 

brown adipocytes employs signalling pathways different 

from those of white adipocytes, with AMPK-mTOR 

cross-talk; and the promotion of BAT development 

by pharmacological activation of AMPK in WAT may 

have potential in treating obesity by acting on energy 

dissipation. 


The major challenges for our research team are: the 

contribution of stress and pro-inflammatory kinases to 

insulin resistance induced by FFA and cytokines, such 

as Tweak and TNF-alpha, in human adipocytes; the 

identification of GRK-2 as a therapeutic target in the 

treatment of type 2 diabetes and adiposity-related disorders 

(the purpose of this study being to investigate in 

vivo the contribution of GRK-2 to insulin action in different 

murine models of insulin resistance); and the role 

of GRK-2 in skeletal muscle differentiation. 

54 CibeRdem

Publications 


Fernández-Veledo S, Vila-Bedmar R, Nieto-Vazquez I, 

Lorenzo M. c-Jun N-terminal kinase 1/2 activation by 

tumor necrosis factor-alpha induces insulin resistance 

in human visceral but not subcutaneous adipocytes: reversal 

by liver X receptor agonists. J Clin Endocrinol 

Metab, 94, 3583-3593 (2009) 

Review 

Fernandez-Veledo S, Nieto-Vazquez I, Vila-Bedmar 

R, Garcia-Guerra L, Alonso-Chamorro M, Lorenzo M. 

Molecular mechanisms involved in obesity-associated 

insulin resistance: therapeutical approach. Arch Physiol 

Biochem, 115 , 227-239 (2009) 

Book chapter 

Lorenzo M, Alonso-Chamorro M, Nieto-Vazquez I. «Skeletal 

muscle insulin resistance: exercise and activation of nuclear 

receptors as pharmacological tools», in Signalling 

networks and therapeutic tools (Monograph XXIV). Real 

Academia Nacional de Farmacia, 279-308 (2009) 

El tejido adiposo blanco como órgano secretor: mecanismos 

moleculares implicados en resistencia/sensibilidad 

a la insulina 

Banco Santander Central Hispano/Universidad 

Complutense de Madrid, PR34/07-1587: 2008-2009 

Principal Investigator: Sonia Fernández 


Redes de señalización celular en enfermedades de etiología 

inflamatoria 

INSINET-CM network, S-SAL/0159/2006: 2007-2010 

Principal Investigator: Margarita Lorenzo 

Private funds 

SYMPHAT: Estudio de la regulación hormonal del 

adipocito del obeso (respuesta adrenérgica y muerte 

celular) y sus aplicaciones en la búsqueda de nuevos 

fármacos 

Projech Science to Technology, 151/2007: 2007-2009 


Lorenzo M, Benito M. «From Insulin Action to Hormonal 

Resistance. Old to Recent Molecular Mechanisms», in 

Type 2 Diabetes Mellitus. Elsevier, 105-129 (2009) 













Mecanismos que conectan la inflamación asociada a la 

obesidad con la resistencia a la insulina 

MICINN, BFU2008-04043: 2009-2011 


Inflamación asociada a obesidad y resistencia a insulina: 

papel de quinasas, fosfatasas y desacetilasas 

Banco Santander Central Hispano/Universidad 

Complutense de Madrid, GR58/08: 2009-2010 


JNK1/2 activation by TNFalpha induces insulin resistance in human 

visceral but not subcutaneous adipocytes: reversal by liver 

X receptor agonists. TNFalpha induces insulin resistance on 

glucose uptake in human visceral but not subcutaneous adipocytes, 

suggesting depot-specific effects of TNFalpha on glucose 

uptake. Activation of JNK1/2 appears to be involved in serine 

phosphorylation of IRS-1 and subsequently insulin resistance on 

glucose uptake, a state that can be reversed by LXR agonists. 


55

Awards 

«Premio Sergio Vidal» to the best biomedical scientific 

report entitled “Hyperinsulinemia induces insulin resistance 

on glucose and lipid metabolism in a human 

adipocytic cell line: paracrine interaction with myocytes”, 

Universidad de Santiago de Compostela (2009) 

Awardee: Sonia Fernández 

«Premio del Consejo General del Colegio Oficial de 

Farmacéuticos» to the report entitled “Pharmacological 

activation of AMPK: a therapeutic approach to combat 

obesity promoting brown fat development”, Real 

Academia Nacional de Farmacia (2009) 

Awardees: Rocío Vila, Sonia Fernández, Margarita 

Lorenzo ■ 

Words for Marga 

Last April, one of our best scientists in the field of biochemistry and molecular biology passed 

away. In remembrance of her, Marga’s research group («her girls» as she liked to call us), 

wanted to take this opportunity to pay a small tribute to a great professional and excellent human 

being and so thank her for everything she did for us over all these years. 

She gave us the chance to take part in her scientific project by inviting us to form part of her 

research group. She was always ready to open the doors of the scientific world to us, she took 

a keen day-to-day interest in our work and our training and did so with uncommon generosity. 

We feel very fortunate to have known her and to have shared with her so many moments, and 

not only of science, because although her work was one of her great passions, Marga was a 

person who knew how to live life and transmitted her joy and enthusiasm to all those around her. 

Her desire to excel was a constant feature of her life. After years of dedication and effort, Marga 

was at a high point in her scientific and teaching career. She dedicated a great part of her life 

to studying the relationship between obesity, inflammation and insulin resistance. Her legacy to 

science will always be present in the great number of her publications in various specialized 

journals, chapters in books and contributions to congresses. In recognition of her work, she 

received various awards from the Real Academia Nacional de Farmacia and other prestigious 

institutions. We shall always remember how she shared her professional achievements with us, 

teaching us that teamwork is one of the keys to professional success. She has had a seminal 

influence and, from her laboratory, we shall try to keep alive her memory and her work, striving 

always to carry on her research project. We hope that we will be up to the task and that Marga, 

wherever she may be, can feel proud of us. 

Marga gave us the opportunity to grow by her side as scientists, but we also learned many other 

things from her: she taught us to love science, to get the most out of congresses, to be practical, 

to be critical of our own work and not be satisfied with second best, to see the positive side of science 

giving it a bit of colour and a touch of glamour, but, above all, to carry on in spite of difficulty. 

Thank you, Marga, for the path you opened up for us with your enthusiasm and perseverance, 

overcoming difficulties and generously sharing your triumphs. You are our example as a human 

being and our scientific guide. 

We shall always carry your memory in our hearts. 

Sonia, Iria, Rocío, Lucía, María, Elena, Loa and Ana 

56 CibeRdem

Molecular mechanisms of insulin resistance and 

sensitivity in peripheral tissues 

Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, Madrid 

www.iib.uam.es 

Principal Investigator Ángela Martínez Valverde Postdoctoral fellow Águeda González, Jesús 

Revuelta Lab technician Soledad Miranda 

Keywords 

Cytokines. Hormone receptors. Insulin action. Insulin 

sensitivity and resistance. Retinopathy. Weight regulation 

and obesity. 


The protein tyrosine phosphatase PTP1B negatively 

modulates insulin signalling in peripheral tissues. 

PTP1B-deficient mice develop insulin hypersensitivity 

in the liver and skeletal muscle. Primary hepatocytes 

lacking PTP1B have increased insulin-induced 

PI 3-kinase/Akt/FoxO1 signalling, a more pronounced 

inhibition of gluconeogenic gene expression, and resistance 

to cell death. Conversely, insulin receptor 

substrate (IRS) 2 null mice have a type 2 diabetic 

phenotype due to hepatic insulin resistance, together 

with beta-cell failure. Hepatocytes from IRS-2 -/- 

mice have severe defects in the activation of the 

PI 3-kinase/Akt/FoxO1 branch of insulin signalling 

and, therefore, insulin fails to repress gluconeogenic 

genes and to protect hepatocytes against cell death. 

Thus, inhibition of PTP1B is a promising strategy by 

which to overcome hepatic insulin resistance due to 

defects in IRS-2 signalling. 


The inhibition of PTP1B by genetic and pharmacological 

approaches in systemic IRS-2-deficient mice as a 

molecular strategy to restore IRS-1-mediated insulin 

signalling and hepatic insulin sensitization. 

The study of the critical nodes of the insulin-signalling 

cascade in human biopsies from patients with nonalcoholic 

hepatic steatosis (NAFLD), steatohepatitis 

(NASH) and hepatitis virus C infection (HCV). 

The effects of insulin sensitization by PTP1B deficiency 

on hepatic regeneration in mice fed on chow or a highfat 

diet: molecular mechanisms involved. 

The effects of PTP1B deficiency on age-induced insulin 

resistance and metabolic damage. 

The effect of PTP1B deficiency on postnatal liver 

growth: alterations in the GH/IGF-1 system. 

The role of S6K1 on hepatocyte survival: feed-back 

mechanisms mediated by IRS proteins. 

The possible beneficial effect of PTP1B inhibition in the 


57

impairment of survival of photoreceptor cells in IRS-2- 

deficient mice. 

Stress signalling pathways in diabetic retinopathy. 


Our expertise is focused on the study of the insulin signalling 

cascade in peripheral tissues either in vivo in 

murine models of insulin resistance or hypersensitivity 

or in vitro in primary or immortalized cells. For the latter, 

we have proven experience in the generation of immortalized 

cell lines from liver and brown adipose tissue. 

These cell lines are valuable tools with which to study 

the unique role of the critical nodes of insulin signalling 

in the metabolic and anti-apoptotic actions of the 

hormone. 


We found that mice with IRS-2 deletion develop impaired 

hepatic insulin signalling and elevated gluconeogenesis, 

whereas mice deficient in PTP1B display 

an opposing hepatic phenotype characterized by increased 

sensitivity to insulin. To define the relationship 

between these two signalling pathways in the liver, we 

used genetic and pharmacological approaches. In the 

livers and islets of hyperglycaemic IRS-2 -/- mice, the expression 

of PTP1B and its association with the insulin 

receptor (IR) were increased. The absence of PTP1B 

in the double mutant IRS-2 -/- /PTP1B -/- mice restored 

hepatic IR/IRS-1-mediated PI 3-kinase/Akt/FoxO1 

signalling and the inhibition of gluconeogenic genes in 

response to insulin. Pharmacological treatment of hyperglycaemic 

IRS-2 -/- mice with resveratrol decreased 

hepatic PTP1B and inhibited its enzymatic activity, 

thereby restoring IR/IRS-1-mediated insulin signalling 

and insulin sensitivity. By regulating the phosphorylation 

state of IR, PTB1B exerts a unique role in the interplay 

between IRS-1 and IRS-2 in the modulation of 

hepatic insulin action. 


To investigate whether PTP1B inhibition or the activation 

of the hystone deacetylase Sirt1 are able to overcome 

hepatic inflammation in female IRS-2-deficient 

mice. 

To investigate the molecular mechanism by which 

PTP1B inhibition accelerates hepatic regeneration in 

mice because it has been shown to be negatively affected 

by obesity and insulin resistance. 

To investigate whether PTP1B inhibition can protect 

photoreceptor cells against apoptosis in IRS-2-deficient 

mice. 

To investigate the stress pathways induced by hyperglycaemia 

and hypoxia in retinal pigmented epithelial 

cells. 

To investigate the effects of PTP1B inhibition on brown 

adipocyte differentiation and in the protection against 

apoptosis induced by pro- and anti-inflammatory stimuli. 

To investigate the stress pathways induced by hyperglycaemia 

and hypoxia in retinal pigmented epithelial cells. 

PTP1B expression and its enzymatic activity are increased in the livers of IRS-2 KO mice. 

58 CibeRdem

Hormonal regulation of adipocyte cell death: applications 

in the design of anti-obesity therapies 

Ministerio de Ciencia e Innovación, PROFIT 2007-0501: 

2007-2010 

Principal Investigator: AM Valverde 

Private funds 

Role of PTP1B on hepatocyte apoptosis 

Hoffmann-La Roche: 2009-2010 

Principal Investigator: AM Valverde ■ 

PTP1B expression is increased in islets of IRS-2 KO mice. 

Publications 


González-Rodriguez A, Alba J, Zimmerman V, Kozma SC, 

Valverde AM. S6K1 deficiency protects against apoptosis 

in hepatocytes. Hepatology, 50, 216-229 (2009) 



Identification of neurodegenerative mechanisms that 

promote the development of diabetic retinopathy: the 

role of insulin signalling and apoptosis 

NEURONET-DIAB: 2009-2010 

Principal Investigators: Deborah Burks, Ángela Martínez 

Valverde, Rafael Simó 



Estudio de los mecanismos moleculares de sensibilidad 

a la insulina en el hígado de ratones dobles nulos 

IRS-2/PTP1B 



Principal Investigator: AM Valverde 


59

Molecular characteristics, and action of incretins, 

in the physiopathology of glucose, lipids and 

bone metabolism 

Fundación Jiménez Díaz, Madrid 

www.fjd.es 

Principal Investigator María Luisa Villanueva-Peñacarrillo Associate researcher Alicia Acitores, 

Nieves González, Isabel Valverde PhD student Irene Gutiérrez, Paola Moreno, Bernardo Nuche 

Lab technician Estrella Martín-Crespo 

Keywords 

Glucose transport. Hormone receptors. Incretins. Insulin 

sensitivity and resistance. Lipid metabolism. 


At present, the research work of our group is mainly focused 

on three aspects: the mechanism of insulin secretion; 

the effects and mechanisms in the action of GLP-1 

(Glucagon-like-peptide 1) -an incretin with antidiabetic 

properties- and also that of GLP-1-homologues peptides; 

and the genetic characteristics, pharmacology and 

function of the human BRS-3 receptor, a possible target 

for the treatment of diabetes and obesity. 

To answer the questions we are permanently asking ourselves, 

we use in vivo and in vitro systems. For the in 

vivo research work, we essentially use rats, in which we 

develop experimental models of insulin resistance and 

diabetes following appropriate well-known protocols. For 

the in vitro studies, we use tissues from rat and man, and 

also primary culture cells. We measure, in most cases, 

parameters involved in glucose and lipid metabolism and 

cellular-signalling enzyme activities. 


The mechanism of insulin secretion. 

The effects and mechanisms in the action of GLP-1 action 

(glucagon-like-peptide 1) -an incretin with antidiabetic 

properties - and also that of GLP-1-homologue peptides, 

on glucose, lipids and bone metabolism. 

The genetic characteristics, pharmacology and function 

of the human BRS-3 receptor, a possible target for the 

treatment of diabetes and obesity. 


The mechanism of the secretion and action of insulin: in 

vivo (human and experimental animal models of insulin 

resistance and diabetes) and in vitro (rat isolated pancreatic 

islets). 

The mechanism of the in vivo action of hormones of intestinal 

origin (GLP-1, GLP-2, …) and related peptides 

(exendines) with influence on glucose and/or lipid metabolism, 

in pancreatic and extrapancreatic tissues from 

man and rat (normal, obese, insulin resistant, type 2 and 

type 1 diabetic states). 

The influence of nutritional components on the 

60 CibeRdem

participation of the secretion of pancreatic and intestinal 

hormones on glucose homeostasis. 

The genetic and pharmacological characteristics of gastrointestinal 

receptors involved in obesity and diabetes. 


A description of the effect of exendine-4 treatment upon 

glucose uptake parameters in rat muscle, in normal and 

type-2 diabetic states. 

A description of the effect of GLP-1 treatment on bone turnover 

in normal, insulin-resistant and type-2 diabetic states. 

A description of the osteogenic action exerted by exendine-4 

in insulin-resistant and type-2 diabetic states. 


The genetic characteristics, pharmacology and function 

of the human BRS-3 receptor, a possible target for the 

treatment of diabetes and obesity. 

The molecular characterization of the GLP-1 receptor in 

extrapancreatic tissues: liver, skeletal muscle and fat. 

The effects of GLP-1 and exendin-4 treatment on glucose 

metabolism and bone turnover in obese states. 

The characteristics of GLP-1 action in diabetic retinal 

pathology. 

Publications 


Arnés L, Moreno P, Nuche-Berenguer B, Valverde I, 

Villanueva-Peñacarrillo ML. Effect of exendin-4 treatment 

upon glucose uptake parameters in rat liver and 

muscle, in normal and type 2 diabetic state. Regul Pept, 

153, 88-92 (2009) 

of Olive Oil and Guar on Fructose-Induced Insulin 

Resistance, in Olives and olive oil in health and disease 

prevention». Elsevier, 132, 1205-1212 (2009) 



Mechanisms of endothelial dysfunction in diabetes: the 

role of amylin and circulating endothelial cells 

ENDODIAB: 2009-2010 

Principal Investigators: Anna Novials, Ramon Gomis, 

María Luisa Villanueva-Peñacarrillo 



Genetic characteristics, pharmacology and function of 

the human BRS-3 receptor, posible target for the treatment 

of diabetes and obesity 

Instituto de Salud Carlos III, FIS CP08/00158: 2009-2011 

Principal Investigator: Nieves González 

Características de las acciones del GLP-1 sobre el metabolismo 

de los tejidos adiposo y óseo, en estados de obesidad, 

sin y con alteración del metabolismo de la glucosa 

Instituto de Salud Carlos III, FIS PI060076: 2006-2009 

Principal Investigator: ML Villanueva Peñacarrillo 

Private funds 

Papel de la Amilina en la disfunción endotelial asociada 

a la diabetes tipo 2. Un modelo experimental 

Mutua de Madrid: 2009-2010 

Principal Investigator: ML Villanueva-Peñacarrillo 

Project coordinator: Leocadio Rodríguez Mañas ■ 

Nuche-Berenguer B, Moreno P, Esbrit P, Dapía S, Caeiro 

JR, Cancelas J, Haro-Mora JJ, Villanueva-Peñacarrillo 

ML. Effect of GLP-1 treatment on bone turnover in normal, 

type 2 diabetic, and insulin-resistant states. Calcif 

Tissue Int, 84, 453-461 (2009) 

Book chapter 

Valverde I, Moreno P, Cancelas J, Prieto PG, Villanueva- 

Peñacarrillo ML, Malaisse WJ. «Effects of an Olive-Oil- 

Enriched Diet on Glucagon-Like Peptide-1, in Olives 

and olive oil in health and disease prevention». Elsevier, 

133, 1213-1220 (2009) 

Villanueva-Peñacarrillo ML, Prieto PG, Cancelas J, 

Sancho V, Moreno P, Malaisse WJ, Valverde I. «Effects 

Representative µCT images of the trabecular areas of the proximal 

femur from normal (N), and also from type 2 diabetic (T2D) 

and insulin-resistant (IR) rats, untreated (saline-control) or treated 

with GLP-1. 


61

Heterogenic and polygenic diseases. Genexartis 

Institut de Recerca Biomèdica, Barcelona 

www.irbbarcelona.org 

Principal Investigator Antonio Zorzano Associate researcher Marta Camps, Anna Gumà, Manuela 

Sánchez-Feutrie, Xavier Testar Postdoctoral fellow Maria Àngels Díaz, Saska Ivanova, Iliana López, Juan 

Pablo Muñoz, Deborah Naon, Montserrat Romero, Jana Sánchez, David Sebastián, Eleonore Sorianello 

Research assistant Ignacio Castrillón, Juan Carlos Monasterio PhD student Guilherme Alves de Lima, 

Ana Paula da Silva Madeira, Víctor Francis, María Isabel Hernández, Vicente Martínez, Caroline Mauvezin, 

Katrin Niifuke, Eduard Noguera, Sónia Pereira, David Sala, Ana Sancho Lab manager Olga Bausà 

Technologist Jessica Segalés 

Keywords 

Genomics. Insulin action. Insulin sensitivity and resistance. 

Transcription factors. Exercise. 


Insulin resistance is a trait common to disorders such 

as type 2 diabetes or obesity. Major factors that participate 

in the development of insulin resistance are 

inflammation, excessive lipid availability, oxidative 

stress, endoplasmic reticulum stress or mitochondrial 

dysfunction. A key step towards the complete understanding 

of type 2 diabetes is the identification of insulin 

resistance susceptibility genes. This will lead to 

the acquisition of therapeutic targets for future drug 

design. 


Our global aim is to determine the molecular mechanisms 

involved in the development of insulin resistance 

and to identify novel insulin resistance and type 

2 diabetes susceptibility genes. The specific research 

lines are: the role of mitochondrial dynamics proteins 

in metabolic homeostasis and in the control of insulin 

resistance; the role of regulators of nuclear gene expression 

in insulin resistance; autophagy, metabolism 

and insulin resistance; and the physiological role of 

neuregulins in skeletal muscle. 


The culture and differentiation of adipose and muscle 

cells; the culture of adipose-tissue-derived stem cells 

and of bone-marrow-derived mesenchymal stem cells; 

the manipulation of gene expression by infection with 

adenoviral and lentiviral viruses and the use of siRNA or 

microRNA vectors; the measurement of dynamic metabolic 

parameters (substrate transport, metabolism and 

oxidation, glucose transporter trafficking, mitochondrial 

function); cell-biology analysis of mitochondria, endoplasmic 

reticulum, and autophagosomes; intracellular 

signalling pathways; the incubation of muscles and of 

isolated adipocytes; and the metabolic phenotyping of 

mice (substrate handling, in vivo respiration, locomotion, 

microCT scanning). 

62 CibeRdem


We demonstrated that morbidly obese type-2 diabetic 

patients show a defect in the regulatory pathways that 

induce genes involved in mitochondrial biogenesis/function. 

We observed that weight loss after biliopancreatic 

diversion exerts a beneficial effect on insulin sensitivity 

via mechanisms that are independent of the expression 

of genes involved in mitochondrial biogenesis/activity. 

We demonstrated that caveolin-1 loss of function reduces 

insulin action in adipose cells through lowered 

stability and diminished expression of insulin receptors 

and GLUT4. 

We identified the expression and secretion of the chemokine 

CXC ligand 5 (CXCL5) in the macrophage fraction 

of white adipose tissue, and demonstrated that 

treatment with recombinant CXCL5 blocks insulin-stimulated 

glucose uptake in muscle in mice. 


To demonstrate that mitochondrial fusion proteins 

modulate metabolic processes and insulin sensitivity in 

tissues. 

To demonstrate a physiological role for neuregulins in 

skeletal muscle. 

To identify novel regulators of gene expression as modulators 

of adiposity and insulin sensitivity. 

To investigate the role of the novel activator of autophagy, 

DOR, on metabolic homeostasis. 

Publications 


Chavey C, Lazennec G, Lagarrigue S, Clapé C, 

Iankova I, Teyssier J, Annicotte JS, Schmidt J, Mataki 

C, Yamamoto H, Sanches R, Guma A, Stich V, Vitkova 

M, Jardin-Watelet B, Renard E, Strieter R, Tuthill A, 

Hotamisligil GS, Vidal-Puig A, Zorzano A, Langin D, 

Fajas L. CXC ligand 5 is an adipose-tissue derived factor 

that links obesity to insulin resistance. Cell Metab, 

9, 339-349 (2009) 

González-Muñoz E, López-Iglesias C, Calvo M, Palacín 

M, Zorzano A, Camps M. Caveolin-1 loss of function 

accelerates glucose transporter 4 and insulin receptor 

degradation in 3T3-L1 adipocytes. Endocrinology, 150, 

3493-3502 (2009) 

Hernández-Alvarez MI, Chiellini C, Manco M, Naon D, 

Liesa M, Palacín M, Mingrone G, Zorzano A. Genes involved 

in mitochondrial biogenesis/function are induced 

in response to bilio-pancreatic diversion in morbidly 

obese individuals with normal glucose tolerance but not 

in type 2 diabetic patients. Diabetologia, 52, 1618-1627 


Ortega FJ, Moreno-Navarrete JM, Ribas V, Esteve 

E, Rodriguez-Hermosa JI, Ruiz B, Peral B, Ricart W, 

Zorzano A, Fernández-Real JM. Subcutaneous fat 

shows higher thyroid hormone receptor-alpha1 gene 

expression than omental fat. Obesity (Silver Spring), 

17, 2134-2141 (2009) 

Review 

Liesa M, Palacín M, Zorzano A. Mitochondrial dynamics 

in mammalian health and disease. Physiol Rev, 89, 

799-845 (2009) 

Yraola F, Zorzano A, Albericio F, Royo M. Structureactivity 

relationships of SSAO/VAP-1 arylalkylaminebased 

substrates. ChemMedChem, 4, 495-503 (2009) 

Zorzano A. Regulation of mitofusin-2 expression in 

skeletal muscle. Appl Physiol Nutr Metab, 34, 433-439, 


Zorzano A, Liesa M, Palacín M. Mitochondrial dynamics 

as a bridge between mitochondrial dysfunction and 

insulin resistance. Arch Physiol Biochem, 115, 1-12 


Zorzano A, Liesa M, Palacín M. Role of mitochondrial 

dynamics proteins in the pathophysiology of obesity 

and type 2 diabetes. Int J Biochem Cell Biol, 41, 1846- 

1854 (2009) 

Zorzano A, Palacín M, Marti L, García-Vicente S. 

Arylalkylamine vanadium salts as new anti-diabetic 

compounds. J Inorganic Biochem, 103, 559-566 (2009) 

Zorzano A, Sebastián D, Segalés J, Palacín M. The molecular 

machinery of mitochondrial fusion and fission: 

An opportunity for drug discovery? Curr Opin Drug 

Discov Devel, 12, 597-606 (2009) 








63






European project 

Transnational Cooperation for the Technological 

Innovation on the Development of Molecules for 

Treatment of Obesity and Diabetes 

SUDOE (European Community Inititative INTERREG 

IV for the Southwestern of Europe), SOE1/P1/E178: 


Principal Investigator and Project coordinator: A Zorzano 

Integration of the system models of mitochondrial 

function and insulin signalling and its application in the 

study of complex diseases 

European Union, Seventh Framework Programme 

(FP7), HEALTH-F4-2008-223450: 2008-2011 

Principal Investigator and Project coordinator: A Zorzano 

Adipose tissue: a key target for prevention of the 

Metabolic Syndrome 

European Science Foundation, COST Action BM0602: 

2007-2011 

Principal Investigator: Antonio Zorzano 

Project coordinator: Jürgen Eckel 


Genetic determinants of the metabolic alterations in 

obesity and/or type 2 diabetes and their participation in 

insulin resistance 



Caracterización de los efectos de las neuregulinas en 

modelos de resistencia a la insulina 



Project coordinator: Anna Gumà 


Molecular basis of metabolic disorders 

Departament d’Innovació, Universitats i Empresa, 

Generalitat de Catalunya, 2009SGR915: 2009-2013 


Patents 

International patent 

Salicylate Conjugates Useful for Treating Metabolic 

Disorders 

Patent application number: US 2009/0298923A1 

Inventors: Mayoux E, Martí L, García-Vicente S, 

Serrano M, Mian A, Zorzano A 

Genmedica Therapeutics (2009) ■ 

Bak localizes in mitochondria. Mouse embryo fibroblasts were transfected with Bak-GFP and with mito-RFP. Images show labelling of mitochondria 

with Bak-GFP (green), mito-RFP (red) and colocalization is indicated in yellow. 

64 CibeRdem

Area 2 

Dyslipidaemia, metabolic syndrome 

and microvascular complications of diabetes

Under this general title, Area 2 includes a wide selection of basic and clinical research topics. A summary would 

include: diabetic dyslipidaemia, eicosanoid research, hyperhomocystenaemia, polycystic ovary syndrome, 

genomic and proteomic analysis of subcutaneous/ abdominal adipose tissue in morbidly obese subjects, chronic 

low-level inflammation and obesity/insulin resistance/type 2 diabetes mellitus, epidemiological, clinical and 

experimental projects, diabetic retinopathy and other topics of diabetic complications. 

Significant contributions by each of the eleven research groups integrated in Area 2 during the year 2009 are 

presented in the following pages. Several of the achievements are worth mentioning here, for example: the 

discovery of key regulatory roles for JNK in lipid droplet formation and inflammatory signalling in human white 

adipose tissue; the discovery of new genes that regulate plasma homocysteine and the association of genotype 

TT with higher levels of homocysteine and lower HDL-cholesterol plasma values; the standardization of imaging 

techniques for the study of adipose tissue distribution and distinct metabolic profiling in adolescent girls with 

polycystic ovary syndrome after different pharmacological interventions; the consolidation of adipose fatty acid 

binding proteins as markers of lipoprotein derangement in familial combined hyperlipidaemia; the identification of 

new genetic variants that affect insulin or blood glucose levels in nondiabetic individuals; the identification of the 

down regulation of the interphotoreceptor retinoid-binding protein in the early stages of diabetic retinopathy; new 

epidemiological evidence showing that the increased prevalence of obesity in free-living populations is associated 

with the type of fatty acids in the diet; the identification of the mechanisms by which statins may prevent the 

development of metabolic syndrome and cardiac hypertrophy; and the optimization of a cell line culture to study 

inflammatory and adipogenic stimulus. 

In 2009, combined research projects between different Area 2 groups initiated in 2008 were continued and new 

inter-group transversal research projects were started. Among the 14 projects financed by CIBERDEM, eight 

included Area 2 researchers: Dr Jesús Balsinde, Dr Francisco Blanco, Dr Rafael Carmena, Dr Federico Soriguer, 

Dr Héctor F Escobar Morreale, Dra Lourdes Ibáñez, Dr Lluís Masana, Dr Manuel Serrano Ríos, Dr Rafael Simó, 

Dr Manuel Vázquez-Carrera and Dr Joan J Vendrell. 

Rafael Carmena 



67

The Eicosanoid Research Division 

Instituto de Biología y Genética Molecular, Consejo Superior de Investigaciones Científicas, Valladolid 

www.balsinde.org 

Principal Investigator Jesús Balsinde Associate researcher María Ángeles Balboa, Olimpio 

Montero Postdoctoral fellow Clara Meana, Gema Pérez PhD student Alma Astudillo, Esperanza 

Esquinas, Luis Gil de Gómez, Lucía Peña, Martín Valdearcos Lab manager Montserrat Duque, 

Yolanda Sáez Lab technician David Balgoma 

Keywords 

Cytokines. Lipid metabolism. Lipid signalling. Metabolic 

syndrome. Phospholipases. 


Numerous signal transduction processes involve lipids 

as signalling molecules. Many of these molecules 

are generated by phospholipases, enzymes that 

cleave ester bonds within phospholipids, and our aim 

is to get a better understanding of their regulation, 

particularly in relation to inflammation and obesity. At 

the Eicosanoid Research Division we combine a wide 

range of chemical, biochemical, biophysical, and molecular 

cell biology techniques to study relevant problems 

pathophysiologically. 


Signalling pathways involved in eicosanoid biosynthesis 

in obesity and inflammation. 

Biosynthesis and degradation of lipid droplets. 

Lipid metabolite analysis by mass spectrometry 

(lipidomics & metabolipidomics). 

Spatiotemporal regulation of phospholipid-metabolic 

enzymes, as studied by advanced microscopy 

techniques. 


Lipid chemistry and biochemistry: separation, identification 

and quantification of glycerolipids and sphingolipids 

by liquid chromatography/mass spectrometry. 

Molecular cell biology: the use of fluorescent tagged 

proteins related to lipid metabolism for subcellular localization 

studies utilizing confocal microscopy. 

Enzymology and pharmacology: manipulation of the 

activity of lipid signalling enzymes both in vivo and in 

vitro by utilizing structurally defined compounds. 


The discovery of key regulatory roles for c-jun 

N-terminal kinases (JNK) in lipid droplet formation and 

inflammatory signalling in human white cells. 

The discovery of a novel cross-talk mechanism of 

68 CibeRdem

egulation of lipid mediator biosynthesis during inflammatory 

signalling. 


To establish pathway-oriented profiling of lipid mediators 

in adipose tissue and circulating white blood cells. 

To characterize the role of lipins (magnesium-dependent 

phosphatidate phosphatases) in regulating the 

formation and/or degradation of lipid droplets. 

To study the putative signalling roles of acyltransferases 

and their relevance to glycerolipid metabolism. 

Publications 


Gubern A, Barceló-Torns M, Barneda D, López JM, 

Masgrau R, Picatoste F, Chalfant CE, Balsinde J, 

Balboa MA, Claro E. JNK and ceramide kinase govern 

the biogenesis of lipid droplets through activation of 

group IVA phospholipase A2. J Biol Chem, 284, 32359- 


Detection of free arachidonic acid by mass-spectrometry. A) 

Deuterated arachidonic acid (from commercial sources); B, naturally-ocurring 

arachidonic acid. 

Gubern A, Barceló-Torns M, Casas J, Barneda D, 

Masgrau R, Picatoste F, Balsinde J, Balboa MA, Claro 

E. Lipid droplet biogenesis induced by stress involves 

triacylglycerol synthesis that depends on group VIA 

phospholipase A2. J Biol Chem, 284, 5697-5708 (2009) 

Ruipérez V, Astudillo AM, Balboa MA, Balsinde J. 

Coordinate regulation of TLR-mediated arachidonic 

acid mobilization in macrophages by group IVA and 

group V phospholipase A2s. J Immunol, 182, 3877- 


Review 

Pérez-Chacón G, Astudillo AM, Balgoma D, Balboa MA, 

Balsinde J. Control of free arachidonic acid levels by 

phospholipases A2 and lysophospholipid acyltransferases. 

Biochim Biophys Acta, 1791, 1103-1113 (2009) 

Book chapter 

Balsinde J, Dennis EA. «Role of phospholipase A2 

forms in arachidonic acid mobilization and eicosanoid 

generation», in Handbook of Cell Signaling, 2nd Edition. 

Bradshaw RA and Dennis EA eds, 1213-1218 (2009) 



Adult adipose tissue-derived progenitor cells: the influ- 

Human macrophages transfected with a lipin1a-GFP construct 

(green fluorescence), immunostained with an antibody against 

adipophilin (red fluorescence), and labelled with DAPI (nuclear 

blue fluorescence) as analysed by confocal microscopy. The image 

shows a tridimensional reconstruction of fluorescence obtained 

from 20 different stacks from a single cell. Lipid droplets 

that are more distal in the cell have more prominent staining with 

adipophilin, while internal lipid droplets have a stronger expression 

of lipin1a. 


69

ence of the clinical phenotype and adipose depot origin 









Una aproximación de lipidómica al estudio de la respuesta 

inmune innata: mecanismos que gobiernan 

la disponibilidad y metabolismo oxidativo de ácido araquidónico 

en macrófagos 


2007-2010 

Principal Investigator: Jesús Balsinde 

Inflamación y obesidad: dos procesos metabólicos regulados 

por una misma enzima; la fosfatasa de ácido 

fosfatídico dependiente de magnesio 

Ministerio de Ciencia e Innovación, SAF2007-60055: 

2007-2010 

Principal Investigator: María A Balboa 


Role of Calcium-independent Phospholipase A 2 

in 

Oxidative Stress 

Junta de Castilla y León, CSI09A08: 2008-2010 

Principal Investigator: Jesús Balsinde ■ 

70 CibeRdem

Metabolic disease and cardiovascular risk 

Hospital de la Santa Creu i Sant Pau, Servei de Bioquímica i Endocrinologia 

www.santpau.cat 

Principal Investigator Francisco Blanco Associate researcher Joan Carles Escolà, Jesús María 

Martín, Antonio Pérez Postdoctoral fellow Josep Julve, Gemma Llaverias, Noemí Rotllan, Juan 

Antonio Sánchez PhD student Elisabeth Rodríguez Lab technician Mireia Lloret, Carme Mayoral, 

Cristina Muñoz, Rosa Roig, David Santos 

Keywords 

Genetics type 2 diabetes. Lipid metabolism. Lipids, lipoproteins. 

Metabolic syndrome. Pathogenic mechanisms. 

The development of experimental-biochemistry and 

molecular-biology techniques or their application to 

clinical laboratory practice (innovation). 


Hyperlipidaemia, type 2 diabetes and other metabolic 

alterations, such as hyperhomocysteinaemia, play an 

important role in determining cardiovascular risk. 

In this context, our group is particularly interested in: 

measuring HDL antiatherogenic functions beyond HDL 

cholesterol; understanding how homocysteine, or its 

related compounds, are related to cardiovascular risk; 

and developing or adopting innovative techniques of 

diagnostic and prognostic value in the context of the 

Clinical Biochemistry Service in which we work. 


The antiatherogenic actions of HDL: measurement and 

value for atherosclerosis prediction. 

The genetics of complex metabolic diseases: hyperlipidaemia, 

type 2 diabetes and hyperhomocysteinaemia. 


HDL: reverse cholesterol transport and antioxidant and 

antiinflammatory actions. 

Transgenic mice, lipoprotein metabolism and atherosclerosis 

susceptibility. 

Biochemical and genetic tests for diabetes and cardiovascular 

diagnosis and risk prediction. 


We participated in the discovery that genes ZNF366 

and PTPRD regulate plasma homocysteine. We discovered: 

that fenofibrate and gemfibrozil differentially 

affect macrophage-specific reverse cholesterol transport; 

that apolipoprotein A-II regulates HDL proteome 

composition; that there is a significantly different SNP 

distribution in two genes located in chromosome 3p 

(this in a case-control study including patients with type 


71

2 diabetes); and that cholesterol metabolism is impaired 

in diabetic retinopathy. 

We also implemented the HFN1alpha and glucokinase 

gene for molecular diagnosis of MODY 2 and MODY3 

in our clinical laboratory. 


To analyse the effects of type 2 diabetes on macrophage-specific 

reverse cholesterol transport and its potential 

reversal. 

To prove the functionality of the four newly identified 

SNPs of NNMT and to study the effects of NNMT gene 

expression in vitro and in vivo. 

In the context of CIBERDEM collaborations: to identify the 

gene/s and polymorphism/s responsible for the linkage 

signal of chromosome 3p in patients with type 2 diabetes; 

to define the changes induced in the HDL structure/function 

of patients with type 2 diabetes treated with a nicotinic 

acid-laropiprant; and to define the importance of the impairment 

of cholesterol metabolism in diabetic retinopathy. 

Publications 


Freixenet N, Remacha A, Berlanga E, Caixàs A, 

Giménez-Palop O, Blanco-Vaca F, Bach V, Baiget M, 

Sánchez Y, Félez J, González-Clemente JM. Serum soluble 

transferrin receptor concentrations are increased 

in central obesity. Results from a screening programme 

for hereditary hemochromatosis in men with hyperferritinemia. 

Clin Chim Acta, 400, 111-116 (2009) 

Mälarstig A, Buil A, Souto JC, Clarke R, Blanco-Vaca F, 

Fontcuberta J, Peden J, Andersen M, Silveira A, Barlera 

S, Seedorf U, Watkins H, Almasy L, Hamsten A, Soria JM; 

Genetic Analysis of Idiopathic Thrombophilia (GAIT) and 

Precocious Coronary Artery Disease (PROCARDIS) consortia. 

Identification of ZNF366 and PTPRD as novel determinants 

of plasma homocysteine in a family-based genome-wide 

association study. Blood, 114, 1417-1422 (2009) 

Rosales C, Gillard BK, Courtney HS, Blanco- 

Vaca F, Pownall HJ. Apolipoprotein modulation of 

A region of the human chromosome 1 showing significant linkage with DM2 and other metabolic disorders. 

72 CibeRdem

streptococcal serum opacity factor activity against human 

plasma high-density lipoproteins. Biochemistry, 

48, 8070-8076 (2009) 

Salord N, Mayos M, Miralda R, Perez A. Respiratory 

sleep disturbances in patients undergoing gastric bypass 

surgery and their relation to metabolic syndrome. 

Obes Surg, 19, 74-79 (2009) 

Review 

Calpe-Berdiel L, Escolà-Gil JC, Blanco-Vaca F. New insights 

into the molecular actions of plant sterols and 

stanols in cholesterol metabolism. Atherosclerosis, 

203, 18-31 (2009) 

Calpe-Berdiel L, Méndez-González J, Blanco-Vaca F, 

Carles Escolà-Gil J. Increased plasma levels of plant 

sterols and atherosclerosis: a controversial issue. Curr 

Atheroscler Rep, 11, 391-398 (2009) 

Escolà-Gil JC, Rotllan N, Julve J, Blanco-Vaca F. In vivo 

macrophage-specific RCT and antioxidant and antiinflammatory 

HDL activity measurements: New tools for 

predicting HDL atheroprotection. Atherosclerosis, 206, 

321-327 (2009) 

Paniagua P, Pérez A. Repercusiones y manejo de la hiperglucemia 

peroperatoria en cirugía cardíaca. Revista 

Española de Anestesiología y Reanimación, 56, 299- 




Cooperative population and database studies for genetic 

association analysis in T2DM and related traits 

INGENFRED: 2009-2010 

Principal Investigators: Rafael Carmena, Francisco 

Blanco, Manuel Serrano Ríos, Federico Soriguer 

Project coordinator: Felipe Javier Chaves 


diabetes 






lipoproteico y en la modulación de las propiedades antiaterigénicas 

de las HDL 

ISCIII, PI081147: 2009-2011 

Principal Investigator: Francisco Blanco 

Efecto de la expresión de NNMT en la concentración 

plasmática de homocisteína y su relación con la aterogénesis 

en modelos animales 

ISCIII, PI071067: 2008-2010 

Principal Investigator: Josep Julve 

Efecto de la activación de PPARalfa y PPARgamma y 

de la inhibición de la PTEC sobre el transporte reverso 

de colesterol específico de macrófagos y las propiedades 

antioxidantes de las HDL 

ISCIII, PI060551: 2007-2009 

Principal Investigator: Joan Carles Escolà 

Private funds 

Efecto de la apolipoproteína apoA-II sobre el metabolismo 

de los triglicéridos en ratones transgénicos y sujetos 

normolipémicos 

Fundación Española de Arterioesclerosis: 2009-2010 

Principal Investigator: Joan Carles Escolà 

Clinical trials 

HOSMIDIA. Manejo de la diabetes mellitus tipo 2 durante 

la hospitalización: Eficacia y factibilidad de las 

pautas fisiológicas de insulinoterapia. Phase IV 

Sanofi-Aventis: 2008-2009 

Coordinator: Antonio Pérez 

INSPIRE ME/IAA. Intra-Abdominal Adiposity study. 

Phase IV 

Sanofi-Aventis: 2007-2010 

Researcher: Antonio Pérez 

Clinical practice guidelines 

Tratamiento de la hiperglucemia en el hospital. 

Documento de consenso 

Medicina Clínica (Barc), 132, 465-475 (2009) 

Sociedad Española de Diabetes (SED) 

Authors: Pérez Pérez A, Conthe Gutiérrez P, Aguilar 

Diosdado M, Bertomeu Martínez V, Galdos Anuncibay 

P, García de Casasola G, Gomis de Barbarà R, Palma 

Gamiz JL, Puig Domingo M, Sánchez Rodríguez A ■ 


Papel de las lipasas que intervienen en el metabolismo 


73

Dyslipidaemia, inflammation and endothelial 

dysfunction 

Servicio de Endocrinología y Nutrición, Fundación Investigación Hospital Clínico Universitario de Valencia 

www.fihcuv.es 

Principal Investigator Rafael Carmena Associate researcher Juan Francisco Ascaso, Miguel 

Catalá, Felipe Javier Chaves, Sergio Martínez Hervás, José Tomás Real Postdoctoral fellow Ana 

Bárbara García, Marta Peiró Lab manager Sebastián Blesa Lab technician Esther Benito, Clara 

María Bixquert, Nieves Brito, Griselda de Marco 

Keywords 

Insulin sensitivity and resistance. Lipid metabolism. 

Macrovascular disease. Metabolic syndrome. Weight 

regulation and obesity. 


Type 2 diabetes carries an elevated cardiovascular 

risk. A significant component of such risk can be attributed 

to diabetic dyslipidaemia, a cluster of plasma 

lipid and lipoprotein abnormalities that are metabolically 

interrelated. Its main characteristics are elevated 

triglycerides, lowered high-density lipoproteins (HDL) 

and raised small, dense low-density lipoproteins (LDL); 

these are referred to as the «atherogenic lipid triad». 

Treatment of these lipid disorders and normalization of 

postprandial lipaemia in these subjects should lead to a 

reduction in cardiovascular risk. 


The degree of arterial damage and age of onset 

of arteriosclerosis varies in patients with primary 

dyslipidaemias or diabetes, indicating the existence of 

other contributing factors. We have investigated the role 

of oxidative stress (OS), inflammation, insulin resistance, 

and prediabetic states as possible candidates. 

Our research lines include: primary hyperlipaemias 

- genetic diagnosis and cardiovascular risk; primary 

mixed hyperlipaemias - insulin resistance and diabetes 

mellitus; postprandial lipaemia and arteriosclerosis in 

insulin-resistant states; insulin resistance, inflammation 

and oxidative stress; diabetic foot - diagnosis, prevention 

and treatment; and genetic factors regulating BMI 

and abdominal obesity. 


Primary hyperlipaemias (autosomal dominant hypercholesterolaemias, 

ADH) - genetic diagnosis and estimation 

of cardiovascular risk. Factors that influence susceptibility 

to premature ischaemic coronary heart disease 

(CHD), i.e.: HDL-C, ApoE genotype, genetic influence 

on cholesterol response to diet and drug treatment, etc. 

Primary mixed hyperlipaemias (familial combined hyperlipidaemia, 

FCH). The role of insulin resistance and 

74 CibeRdem

OS in diabetes and cardiovascular risk. The response 

of inflammatory markers and OS following an oral fat 

load. 

Postprandial lipaemia - the effect of an oral fat load on 

inflammation and oxidative stress in abdominal obesity 

and insulin-resistant states. 


Monogenic hypercholesterolaemias: we studied the association 

of C677T polymorphism in the MTHFR gene, high 

homocysteine (Hcy) and low HDL cholesterol plasma values 

in heterozygous familial hypercholesterolaemia. We 

found that the genotype TT and higher plasma Hcy levels 

were associated with lower HDL-C plasma values. 

Oxidative stress (OS) in FCH and its correlation with insulin 

resistance: we have detected increased oxidative 

stress levels and normal antioxidant enzyme activity in 

circulating mononuclear cells from patients with familial 

hypercholesterolaemia. 

Moreover, we have demonstrated that increased plasma 

xanthine oxidase activity is related to nuclear factor 

kappa beta activation and inflammatory markers in familial 

combined hyperlipidaemia. 


To study OS and NFkB activity in mononuclear cells at 

genetic and biochemical levels. 

To correlate studies between xanthine oxidase activity 

with inflammation and insulin resistance. 

To study postprandial lipaemia in FH subjects: its influence 

on inflammatory markers and OS. 

To collaborate with other CIBERDEM groups to study 

epidemiological genetic aspects related to metabolic 

diseases and diabetes mellitus. 

To collaborate with other CIBERDEM groups to characterize 

low LDL syndrome in type 2 Diabetes. 

To continue collaboration with a Valencia group, the 

CIBER de Fisiopatología de la Obesidad y Nutrición. 

To become a member of the CAIBER and the Instituto 

de Investigación Sanitaria, Hospital Clínico Universitario 

de Valencia, both at preparatory stages. 

To collaborate with Dr Deborah Burks: characterization 

of adipocytes in familial combined hyperlipidaemia. 

Publications 


Real JT, Martinez-Hervas S, Garcia-Garcia AB, Chaves 

FJ, Civera M, Ascaso JF, Carmena R. Association of 

C677T polymorphism in MTHFR gene, high homocysteine 

and low HDL cholesterol plasma values in heterozygous 

familial hypercholesterolemia. J Atheroscler 

Thromb, 16, 815-820 (2009) 

Ricart W, López J, Mozas J, Pericot A, Sancho MA, 

González N, Balsells M, Luna R, Cortázar A, Navarro 

P, Ramírez O, Flández B, Pallardo LF, Hernández A, 

Ampudia J, Fernández-Real JM, Hernández-Aguado I, 

Corcoy R; Spanish Group for the study of the impact 

of Carpenter and Coustan GDM thresholds. Maternal 

glucose tolerance status influences the risk of macrosomia 

in male but not in female fetuses. J Epidemiol 

Community Health, 63, 64-68 (2009) 

Review 

Atar D, Carmena R, Clemmensen P, K-Laflamme A, 

Wassmann S, Lansberg P, Hobbs R. Clinical review: impact 

of statin substitution policies on patient outcomes. 

Ann Med, 41, 242-256 (2009) 

Book chapter 

Ascaso JF. «Dislipemia diabética. Actitud diagnóstica 

y tratamiento», in La Diabetes Mellitus en la Práctica 

Clínica. Editorial Médica Panamericana, 277-286 (2009) 

Ascaso JF, Real JT, Arbona C. «Técnicas de tratamiento 

poco frecuentes o en fase de investigación (plasmaféresis, 

terapia génica) en las dislipemias», in Manual 

del Residente de Endocrinología. Ed. SEEN, 969-981 


Carmena R. «Aterogénesis como base de la macroangiopatía 

diabética», in La Diabetes Mellitus en la 

Práctica Clínica. Editorial Médica Panamericana, 297- 


Carmena R. «Dyslipemia in Type 2 Diabetes Mellitus», 

in Type 2 Diabetes Mellitus. Elsevier, 219-230 (2009) 

Carmena R. «La enfermedad ya no es lo que era: de 

las entidades nosológicas a los factores de riesgo, un 

siglo de cambios», in La Medicina del Futuro. Capítulo 

Español del Club de Roma, 145-156 (2009) 







75




Characterization of low HDL syndrome in type 2 diabetes 







CAIBER de Unidades Centrales de Investigación 

Clínica y en Ensayos Clínicos 

Instituto de Salud Carlos III, CAI08/01/0039: 2009-2012 

Principal Investigator: Rafael Carmena 

Project coordinator: Esteban Morcillo 

Daño orgánico en la diabetes ellitus tipo 2 y prediabetes: 

factores de riesgo e influencia de los sistemas reninaangiotensina-aldosterona 

y óxido nítrico-estrés oxidativo 

Instituto de Salud Carlos III, PI07/0497: 2008-2010 

Principal Investigator: Francisco Javier Chaves 


Regulación del IMC, de la circunferencia abdominal, 

del desarrollo de obesidad y de obesidad central 

Conselleria d’Educació, Generalitat Valenciana, 

PROMETEO/2009/029: 2009 

Principal Investigator: Rafael Carmena 

Estudio del efecto de una sobrecarga oral con grasa 

insaturada sobre el estrés oxidativo en la obesidad 

abdominal 

Conselleria de Sanitat, Generalitat Valenciana, GE- 

010/09: 2009 

Principal Investigator: Sergio Martínez Hervás 

Patents 

National patent 

Marcadores genéticos del riesgo de sufrir reestenosis 

Patent application number: 200900507 

Inventors: Andrés V, Silvestre C, Fernández P, Sánchez 

PL, Fernández-Avilés F, Chaves FJ 

Fina Biotech, SLU (2009) ■ 

SNPlex Analysis. 

76 CibeRdem

Diabetes, Obesity and Reproductive Endocrinology 

Hospital Universitario Ramón y Cajal and Universidad de Alcalá, Madrid 

www.hrc.es 

Principal Investigator Héctor F Escobar Morreale Associate researcher Francisco Álvarez, María Rosa 

Insenser, Manuel Luque, María Ángeles Martínez, Rafael Montes, Belén Roldán, José Luis San Millán 

PhD student Macarena Alpañés Lab technician Elena Fernández 

Keywords 

Biomarkers and Imaging. Cytokines. Insulin sensitivity 

and resistance. Polycystic ovary syndrome. Proteomics. 


The polycystic ovary syndrome (PCOS) is the most 

common metabolic disorder in women of reproductive 

age. A disorder of complex multigenic aetiology, 

in which predisposing and protective genomic variants 

interfere with strong environmental influences, PCOS 

is characterized by the association of androgen excess 

with disordered ovarian function and/or morphology. 

Androgen excess determines an abnormal deposition 

of body fat which, by favouring abdominal adiposity and 

insulin resistance, predisposes these women to diabetes 

later in life. 


The influence of the balance between androgens and 

oestrogens on the development of abdominal adiposity 

and visceral adipose tissue dysfunction in humans as 

pathogenetic factors of insulin resistance and diabetes, 

including: 1) an integrated approach to the influence of 

sex hormones on the amount and dysfunction of visceral 

and subcutaneous fat as studied by clinical research, 

molecular genetics, molecular biology, genomics, proteomics 

and metabolomics; and 2) the identification of 

pathogenetic markers of diabetes in severe obesity and 

predictors of diabetes remission after bariatric surgery. 


Clinical research; statistics; clinical biochemistry; molecular 

biology; molecular genetics; genomics; proteomics. 


We have standardized the ultrasound-based imaging 

techniques needed to quantify adipose tissue depots 

in men and women and started their application to the 

study of the influence of sex hormones on adipose tissue 

distribution and dysfunction. We have started highthroughput 

genotyping of candidate SNPs for population-based 

case-control studies of PCOS and related 


77

disorders. Finally, we have initiated several collaborations 

with other CIBERDEM groups. 


To complete the ongoing collaboration with the 

CIBERDEM Metabolomics Platform in conducting 

comparative studies on PCOS plasma samples and in 

standardizing LC-MS and GC-MS techniques for the 

correct measurement of circulating testosterone in children 

and women. 

To complete large population- and clinical-based molecular 

genetic studies on PCOS using high-thoughput 

SNP analysis. 

To complete the ongoing DIASOBS project financed by 

CIBERDEM. 

Publications 


Escobar-Morreale HF, Luque-Ramírez M, San-Millán 

JL. Serum visceral adipose tissue-derived serine protease 

inhibitor concentrations in human obesity and polycystic 

ovary syndrome. Diabetes Care, 32, e6 (2009) 

Luque-Ramírez M, Alvarez-Blasco F, Escobar-Morreale 

HF. Antiandrogenic contraceptives increase serum adiponectin 

in obese polycystic ovary syndrome patients. 

Obesity (Silver Spring), 17, 3-9 (2009) 

Luque-Ramírez M, Mendieta-Azcona C, Alvarez- 

Blasco F, Escobar-Morreale HF. Effects of metformin 

versus ethinyl-estradiol plus cyproterone acetate on 

ambulatory blood pressure monitoring and carotid intima 

media thickness in women with the polycystic ovary 

syndrome. Fertil Steril, 91, 2527-2536 (2009) 

Luque-Ramírez M, Mendieta-Azcona C, del Rey 

Sánchez JM, Matíes M, Escobar-Morreale HF. Effects 

of an antiandrogenic oral contraceptive pill compared 

with metformin on blood coagulation tests and endothelial 

function in women with the polycystic ovary 

syndrome: influence of obesity and smoking. Eur J 

Endocrinol, 160, 469-480 (2009) 

Martínez-García MA, Luque-Ramírez M, San-Millán 

JL, Escobar-Morreale HF. Body iron stores and glucose 

intolerance in premenopausal women: role of hyperandrogenism, 

insulin resistance, and genomic variants 

related to inflammation, oxidative stress, and iron metabolism. 

Diabetes Care, 32, 1525-1530 (2009) 






weight loss 




J Vendrell 



Influencia de los andrógenos en el desarrollo de la adiposidad 

abdominal y de la disfunción metabólica del tejido 

adiposo visceral en humanos, como factores etiopatogénicos 

de la resistencia insulínica y la diabetes 

Insitituto de Salud Carlos III, Fondo de Investigación 

Sanitaria, PI080944: 2009-2011 

Principal Investigator: Héctor F Escobar Morreale 

Image showing two-dimensional electrophoresis of human visceral 

adipose issue. 


Protocolo de investigación sobre el perfil de riesgo 

cardiovascular asociado a mujeres con síndrome de 

ovario poliquístico o hiperandrogenismo ovulatorio, y 

evolución del mismo durante el tratamiento con metformina 

frente a un anticonceptivo oral más un antiandrógeno 

(espironolactona). Phase IV 


78 CibeRdem

Name of the participants: HF Escobar Morreale (PI), 

M Luque-Ramírez, M Alpañés (researchers) 


The Androgen Excess and PCOS Society criteria for the 

polycystic ovary syndrome: the complete task force report 

Fertil Steril, 91, 456-488 (2009) 

Authors: Azziz R, Carmina E, Dewailly D, Diamanti- 

Kandarakis E, Escobar-Morreale HF, Futterweit W, 

Janssen OE, Legro RS, Norman RJ, Taylor AE, Witchel SF 

Awards 

«Premio Lilly sobre obesidad», Fundación de la Sociedad 

Española de Endocrinología y Nutrición (2009) 

Awardee: Manuel Luque-Ramírez 

«Premio Elsevier-Doyma Revista Endocrinología y 

Nutrición», Fundación de la Sociedad Española de 

Endocrinología y Nutrición (2009) 

Awardee: Héctor F Escobar Morreale ■ 

Predictive factors of indices of insulin sensitivity, secretion and disposition in premenopausal women with polycystic ovary syndrome 

as opposed to premenopausal women without androgen excess. Fertil Steril (2010). 


79

Prenatal growth restriction and subsequent risks 

for type 2 diabetes and cardiovascular risk 

Hospital Sant Joan de Déu, Universitat de Barcelona 

www.hsjdbcn.org 

Principal Investigator Lourdes Ibáñez Associate researcher Paula Casano, María Victoria Marcos, 

Carme Valls Postdoctoral fellow Marta Díaz PhD student Giorgia Sebastiani Lab technician Jordi 

Guardiola, Maria Teresa Miranda 

Keywords 

Cytokines. Insulin sensitivity and resistance. Metabolic 

syndrome. Paediatrics. Prevention of type 2 diabetes. 


About 3% of human foetuses are born small for gestational 

age (SGA). The vast majority of SGA infants develop 

enough catch-up growth to normalize their body 

size by the age of 2 years. In the past, longitudinal studies 

have discovered that SGA-catch-up children tend 

to become insulin resistant and viscerally adipose by 

the age of 4-6 years, even if not obese; these features 

are accompanied by an abnormal adipokine profile. 

Beyond the age of 8 years, SGA children tend to experience 

pubertal development with early onset and rapid 

progression which may lead to a lower adult stature. 

Being postnatally overweight increases each of the described 

anomalies. 

The association between SGA catch up and subsequent 

postnatal endocrine-metabolic abnormalities has 

become a hot topic, mainly due to the link to increased 

cardiovascular risk and type 2 diabetes in adult life, and 

to the potential for detecting early risk markers which 

allow the implementation of preventive strategies in 

childhood. 

Our research line has focused on the search for new 

single nucleotide polymorphisms influencing body 

composition and weight gain in the first months of 

life, and on the assessment of inflammation markers, 

body composition and abdominal fat partitioning 

and their relationships with both birthweight and the 

subsequent development of insulin resistance, and 

of advanced puberty and ovarian hyperandrogenism 

in girls. 

Preventative strategies including the administration of 

insulin sensitizers in populations at risk are ongoing. 


The influence of early nutrition on growth patterns, 

endocrine-metabolic profile and future cardiovascular 

risks in SGA newborns. 

The association of specific SNPs with catch-up growth, 

body composition and abdominal fat partitioning in 

SGA children. 

80 CibeRdem

The usefulness of insulin sensitizers as modifiers of 

pubertal onset and progression in SGA girls with advanced 

and rapidly progressive puberty. 

The effects of low-dose combinations of insulin sensitizers 

and antiandrogens on cardiovascular risk parameters 

in adolescents with ovarian hyperandrogenism, 

hyperinsulinism, and cardiovascular risk. 


SGA, postnatal catch-up growth and subsequent risks 

for type 2 diabetes and cardiovascular disease - genetic 

and environmental influences. 

Early-onset metabolic syndrome, hyperandrogenism 

and the benefits of early insulin sensitization. 

Ovarian hyperandrogenism, hyperinsulinism, adipose 

body composition and the benefits of combined 

low-dose insulin sensitizing and antiandrogen 

therapy. 


The efficacy of prepubertal insulin sensitization in insulin 

sensitivity and in the normalization of the endocrinemetabolic 

profile, body composition, pubertal milestones 

and final height in girls born SGA. 

Associations between an SNP in the STK11 gene 

and meformin efficacy in girls with hyperinsulinaemic 

hyperandrogenism. 

Distinct metabolic profiling in adolescents and young 

women with hyperinsulinaemic hyperandrogenism 

after low-dose pioglitazone-flutamide-metformin 

therapy. 

Longitudinal changes in body composition, adipokine 

patterns and insulin sensitivity in SGA infants and 

children. 


To explore new clinical and genetic risk markers for 

developing excessive weight gain, hyperinsulinism and 

metabolic syndrome in SGA children. 

Therapeutic and preventative interventions in paediatric 

entities associated with insulin resistance. 

Insights into adipogenesis and the adipokine profile in 

subcutaneous adipose tissue samples from adolescents 

with hyperinsulinaemic hyperandrogenism treated 

with insulin sensitizers. 

Metabolomic studies in SGA-catch-up children receiving 

preventative metformin, and genetic expression in 

placentas of SGA pregnancies. 

Publications 


Ibáñez L, Lopez-Bermejo A, Diaz M, Angulo M, 

Sebastiani G, de Zegher F. High-molecular-weight adiponectin 

in children born small- or appropriate-for-gestational-age. 

J Pediatr, 155, 740-742 (2009) 

Ibáñez L, López-Bermejo A, Díaz M, Enríquez G, del 

Río L, de Zegher F. Low-dose pioglitazone and lowdose 

flutamide added to metformin and oestro-progestagens 

for hyperinsulinaemic women with androgen 

excess: add-on benefits disclosed by a randomized 

double-placebo study over 24 months. Clin Endocrinol 

(Oxf), 71, 351-357 (2009) 

Ibáñez L, López-Bermejo A, Díaz M, Marcos MV, 

Casano P, de Zegher F. Abdominal fat partitioning and 

high-molecular-weight adiponectin in short children 

born small for gestational age. J Clin Endocrinol Metab, 

94, 1049-1052 (2009) 

Ibáñez L, Lopez-Bermejo A, Díaz M, Suárez L, de Zegher 

F. Low-birth weight children develop lower sex hormone 

binding globulin and higher dehydroepiandrosterone sulfate 

levels and aggravate their visceral adiposity and hypoadiponectinemia 

between six and eight years of age. 

J Clin Endocrinol Metab, 94, 3696-3699 (2009) 

Review 

de Zegher F, López-Bermejo A, Ibáñez L. Adipose 

tissue expandability and the early origins of PCOS. 

Trends Endocrinol Metab, 20, 418-423 (2009) 

Ibáñez L, Díaz R, López-Bermejo A, Marcos MV. 

Clinical spectrum of premature pubarche: Links to metabolic 

syndrome and ovarian hyperandrogenism. Rev 

Endocr Metab Disord, 10, 63-76 (2009) 

Editorial 

de Zegher F, Ibáñez L. Early origins of polycystic ovary 

syndrome: hypotheses may change without notice. J 

Clin Endocrinol Metab, 94, 3682-3685 (2009) 

de Zegher F, Ibáñez L. Low-dose flutamide for women 

with androgen excess: anti-androgenic efficacy and hepatic 

safety. J Endocrinol Invest, 32, 83-84 (2009) 

Book chapter 

Ibáñez L, Potau N. «Hiperandrogenismo: hirsutismo 

y ovario poliquístico», in Tratado de endocrinología 

pediátrica, 4th Edition. McGraw-Hill, 609-617 (2009) 


81







Lluís Masana 



Influence of early feeding in neurodevelopment and in 

subsequent cardiovascular risks in infants born small 

for gestational age 

Instituto de Salud Carlos III, Fondo de Investigación 

Sanitaria, PI08/0443: 2008-2010 

Principal Investigator: Lourdes Ibáñez 

Effects on endocrine-metabolic parameters and body 

composition of the addition of low-dose pioglitazone to 

combined metformin+flutamide therapy in young women 

with ovarian hyperandrogenism, hyperinsulinism, 

and cardiovascular risk 


Sanitaria, PI07/90105: 2007-2009 


Effect of prenatal growth restraint and putative thrifty 

genes on size at birth and on body composition, and endocrine-metabolic 

parameters during the first 2 yrs of life 


Sanitaria, PI05/2405: 2005-2009 



Suport a Grups de Recerca 

Generalitat de Catalunya, AGAUR, 2009 SGR 828: 



Private funds 

Endocrine-metabolic profile and body composition in 

infants born large-for-gestational age 

Hospital Sant Joan de Déu, AFR 09/006: 2009- 

2010 


Ovarian hyperandrogenism and polycystic ovaries in 

adolescence: influence of birthweight and postnatal 

body mass index. 

Hospital Sant Joan de Déu, AFR 08/004: 2008-2010 



Ethynil-estradiol-cyproterone acetate versus low-dose 

pioglitazone + flutamide + metformin in adolescents 

with hyperinsulinemic ovarian hyperandrogenism: 

Effects on parameteres of chronic inflammation and on 

risk factors of type 2 diabetes and cardiovascular risk. 

Phase II 


Sanitaria, PI09/90444: 2009-2011 

Name of the participants: Ibáñez L (PI), Diaz M, 

Casano P, López-Bermejo A, Marcos MV, Mir I, Moran 

E, Salvador C (researchers) 

Circulating HMW adiponectin (left panels) and body fat fraction (%) (right panel) in longitudinally studied appropriate-for-gestationalage 

(AGA) children (n=22; open diamonds) and small-for-gestational-age (SGA) children (n=29; closed diamonds). For Z-score values, 

the corresponding results in AGA controls were used as reference. *p

Endocrine-metabolic and body composition effects of 

metformin administration in prepubertal children with a 

low birthweight for gestational age, postnatal catch-up 

growth and risk markers for the metabolic syndrome. 

Phase II 


Sanitaria, EC08/00160: 2008-2010 

Name of the participants: Ibáñez L (PI), Casano P, Diaz 

M, Valls C, del Rio L, Marcos MV, Enríquez G, Sebastiani 

G, Hollenberg G, Fortea E, Cortés R (researchers) 

Comparative study of subcutaneous insulin pump, 

glargine insulin and NPH in diabetic children aged 

0-6 yr. Phase II 


Sanitaria, EC07/90900: 2007-2009 

Name of the participants: Torres M (PI), Casano 

P, Díaz R. Jaramillo A, Anuita C, Gómez A, Marin S 

(researchers) 

Awards 

«VIII Premio Frederik Paulsen de Investigación en 

Endocrinología Pediátrica», Sociedad Española de 

Endocrinología Pediátrica. Best published paper: 

“Gender specificity of body adiposity and circulating 

adiponectin, visfatin, insulin, and insulin growth factor-I 

at term birth: relation to prenatal growth” (2009) 

Awardees: Ibáñez L, Sebastiani G, Diaz M, López- 

Bermejo A, Gómez-Roig MD, de Zegher F 

«Premio Merck-Serono de Investigación», Sociedad 

Española de Endocrinología Pediátrica. Accésit, paper: 

“Metformin treatment for four years to reduce total 

and visceral fat in low birth weight girls with precocious 

pubarche” (2009) 

Awardees: Ibáñez L, López-Bermejo A, Diaz M, Marcos 

MV, de Zegher F 

«XVIII Convocatòria de Premis de Recerca», Hospital 

Sant Joan de Déu. Best Oral Presentation: “Pubertal 

metformin therapy to reduce total, visceral and hepatic 

adiposity beyond puberty”. Endocrine Society, 

Bench to Bedside Pediatric Endocrinology Session 


Awardees: Ibáñez L, López-Bermejo A, Diaz M, Marcos 

MV, de Zegher F ■ 


83

Lipids and Arteriosclerosis Research Unit 

Institut d’Investigació Sanitària Pere Virgili, Hospital Universitari Sant Joan de Reus 

www.iispv.cat 

Principal Investigator Lluís Masana Research director Josep Ribalta, Rosa Solà Senior researcher 

Anna Cabré, Joan Carles Vallvé Associate researcher Antoni Castro, Núria Plana Nutritionist Jordi 

Merino PhD student Gemma Aragonès, Úrsula Catalán, Raimon Ferré, Cecilia González, Marta 

González, Alfons Horra, Iolanda Lázaro, Laia Pons, Noemí Serra, Rosa Maria Valls Lab manager 

Josefa Girona Lab technician Mercedes Heras (head), Carme Buixadera, Sara Fernández, Roser 

Rosales Administrative staff Sílvia Solé 

Keywords 

Biomarkers and Imaging. Endothelium. Lipid metabolism. 

Lipids, lipoproteins. Macrovascular disease. 


Diabetic (atherogenic) dyslipidaemia (AD) is characterized 

by high triglycerides, low HDL and small and dense 

LDL. Additionally, there are qualitative features not detected 

in routine laboratory analyses. The mechanisms 

behind AD are probably related to adipose tissue and 

hepatic dysfunction including an increased release of 

fatty acids leading to hepatic VLDL hypersecretion. We 

aim to characterize the process, its pathogenic determinants, 

the genetic predisposition markers, and vascular 

lesion mechanisms. 


Atherogenic dyslipidaemia in diabetes, obesity and 

metabolic syndrome. 

The characterization of plasma lipoprotein subclasses 

by NMR, metabolomics and lipidomics. 

Adipose tissue dysfunction as a major determinant. 

The role of fatty-acid-binding proteins (FABPs) and 

the alteration of their metabolic pathways including the 

transcription factors involved in the process. 

Fatty acids and adipokine-induced endothelial 

dysfunction. 

AD and subclinical atherosclerosis. 

The genetic determinants of AD and uncontrolled lipolysis. 

The impact of nutrition. 


The clinical assessment of diabetic, obese and MS patients 

with alterations of lipid metabolism. 

NMR lipoprotein subclasses, remnant lipoproteins. 

Subclinical atherosclerosis assessment by sonographic 

methods (IMT) and endothelial function studies. 

Cell-culture models to study lipid metabolism and arteriosclerosis 

mechanisms. 

Association studies of genetic polymorphisms related 

to abnormalities in lipid metabolism. 

Nutritional intervention trials. 

Studies of the metabolic impact of nutrients. 

84 CibeRdem


Plasma levels of adipose fatty-acid-binding proteins 

are consolidated as markers of lipoprotein derangement 

also in genetic processes like FCHL. 

In diabetic and metabolic syndrome patients, different 

genetic conditioning works synergically to induce AD as 

RBP4 and Apo AV. 

Apo H can be considered a crossroads in the vascular 

disease of diabetic and obese patients. 

IMT is an important tool for assessing CV risk in diabetics, 

MS and genetic hyperlipaemic patients. 

PUFA interferes with cholesterol absorption mechanisms 

at a genetic level. 


To study the following: a better characterization of AD focusing 

on the «Low HDL» syndrome; the clinical impact 

of endothelial function assessment by peripheral artery 

tonometry (PAT) and its relation to biochemical markers; 

FABPs metabolic pathways - their role and general function 

in plasma; the role of adipose tissue lipolytic function 

as a cause of AD; the relationship between inflammation 

and endothelial function plasma markers and peripheral 

artery tonometry in diabetics; and the antiatherogenic 

properties of olive oil derived molecules. 

Publications 


Cardona F, Guardiola M, Queipo-Ortuño MI, Murri 

M, Ribalta J, Tinahones FJ. The -1131T>C SNP of 

the APOA5 gene modulates response to fenofibrate 

treatment in patients with the metabolic syndrome: a 

postprandial study. Atherosclerosis, 206, 148-152 (2009) 

Horra A, Salazar J, Ferré R, Vallvé JC, Guardiola M, 

Rosales R, Masana L, Ribalta J. Prox-1 and FOXC2 

gene expression in adipose tissue: A potential contributory 

role of the lymphatic system to familial combined 

hyperlipidaemia. Atherosclerosis, 206, 343-345 (2009) 

Jarauta E, Junyent M, Gilabert R, Plana N, Mateo-Gallego 

R, de Groot E, Cenarro A, Núñez I, Coll B, Masana L, 

Ros E, Civeira F. Sonographic evaluation of Achilles tendons 

and carotid atherosclerosis in familial hypercholesterolemia. 

Atherosclerosis, 204, 345-347 (2009) 

Suárez M, Romero MP, Macià A, Valls RM, Fernández 

S, Solà R, Motilva MJ. Improved method for identifying 

and quantifying olive oil phenolic compounds and 

their metabolites in human plasma by microelution solid-phase 

extraction plate and liquid chromatographytandem 

mass spectrometry. J Chromatogr B Analyt 

Technol Biomed Life Sci, 877, 4097-4106 (2009) 







Lluís Masana 



diabetes 

Metabolism and Vascular Medicine Laboratory. 


85







Aceite de oliva virgen y función de las lipoproteínas de 

alta desnsidad (HDL), un modelo de preparación especializada 

de un alimento funcional 

Ministerio de Ciencia e Innovación, AGL2009- 

13517-C03-03: 2008-2012 

Principal Investigator: Rosa Solà 

Researchers: Lluís Masana, Núria Plana, Raimon Ferré 

Awards 

«Premis Grup Sagessa 2008 en l’àmbit de RECERCA 

CLÍNICA», Grup Sagessa (2009) 

Awardees: Lluís Masana, Núria Plana, Raimon Ferré 

«Premis Grup Sagessa 2008 en l’àmbit de RECERCA 

BÀSICA», Grup Sagessa (2009) 

Awardees: Lluís Masana, Anna Cabré ■ 

Dislipemia Aterógena de la Obesidad, Síndrome 

Metabólico y Diabetes tipo 2: Caracterización 

Metabólica y Mecanismos Patogénicos 

FIS, PI081409: 2008-2011 


Associate investigator: Jesús Brezmes 

Caracterización bioquímica, metabólica y genética de la 

hipertrigliceridemia asociada a alto riesgo cardiovascular 

FIS, PI081579: 2008-2011 

Principal Investigator: Josep Ribalta 

Associate investigator: Nicolau Cañellas 

Metodologías para el diseño, evaluación y validación 

de alimentos funcionales en la prevención de enfermedades 

cardiovasculares y del Alzheimer 

Ministerio de Industria, Turismo y Comercio, Programa 

CENIT, La Morella Nuts SA: 2006-2009 

Principal Investigator: Rosa Solà 

Private funds 

Banco Nacional Enfermedades Metabólicas 

Genoma España: 2007-2009 



EFC6910. Estudio multicentrico, doble ciego, randomizado 

de 12 meses de duracion controlado con placebo. 

Phase III 


Researchers: Lluís Masana, Núria Plana, Raimon Ferré 

MK-0524A. Estudio multicéntrico aletorizado, doble 

ciego, con grupos paralelos y de 12 semanas de tratamiento. 

Phase III 

Merck Sharp & Dohme: 2008-2009 

86 CibeRdem

Diabetobe 

Hospital Clínico San Carlos, Madrid 

www.madrid.org 

Principal Investigator Manuel Serrano Ríos Associate researcher María Teresa Martínez Larrad, 

Jesús Álvarez Fernández-Represa, Arturo Corbatón, Vicente Estrada, Cristina Fernández Research 

assistant Covadonga Caso, Bernat Jiménez, Carina Zabena Lab technician Ángeles Asensio, 

Carmen Obiang, Milagros Pérez, Noelia Rodríguez Administrative staff María del Mar González 

Keywords 

Epidemiology. Genetics type 2 diabetes. Genomics. 

Metabolic syndrome. Proteomics. 


We are currently carrying out an extensive genetic epidemiology 

population-based study along four lines: a) a 

candidate gene approach combined with GWAS strategies 

as related to relevant phenotypic features of obesity 

(subcutaneous/visceral), insulin resistance, type 2 

diabetes and metabolic syndrome; b) transcriptomic 

and proteomic analyses of subcutaneous/visceral adipose 

tissue in morbidly obese patients with or without 

diabetes mellitus or glucose intolerance; c) HIV - lipodystrophy 

as related to either therapy naivety or the impact 

of current VIH treatment, including «new» C-V risk 

factors; d) studies C-V risk factors have been carried 

out with regard to obese children. 


Nutritional primary prevention of type 1 diabetes in 

children (TRIGR). 

The genomic and proteomic study of subcutaneous/ 

abdominal adipose tissue and its relationship to type 2 

diabetes and obesity. 

Genes and inflammatory markers in children with obesity 

and/or metabolic syndrome. 

The analysis of the changing profile of circulating adipokines 

and insulin-resistance status and genetics in 

HIV naïve patients and those undergoing retroviral 

treatment. 

Polycystic ovary syndrome and obesity. 


Genetic epidemiology study. Gene polymorphisms in 

insulin resistance and its relationship to type 2 diabetes 

and obesity. Gene expression and proteomics 

of subcutaneous/visceral adipose tissue, muscle and 

liver from surgically treated obese patients (bariatric 

surgery). Genetic and inflammatory markers in obese 

children. RIA/EIA technology for measuring hormones 

and citokynes. Lipodystrophy and insulin resistance in 

HIV/AIDS. 


87


International collaboration (MAGIC) - we identified 9 

new genetic variants that affect blood glucose levels in 

non-diabetic individuals, and one which affects insulin 

levels. 

A proteomic study in morbidly obese patients looking 

at the proteins related to stress response suggests 

that the damage caused in subcutaneous adipose tissue 

revealed by impaired selective protein expression 

levels correlated to higher adiposity. HIV - we studied 

the TCF7L2 gene and our results suggest that 

rs12255372 T allele may be associated with the development 

of hyperglycaemia and insulin resistance 

independently of BMI as well as with prolonged antiretroviral 

treatment. 


The study of genomic/proteomic profiling in subcutaneous/visceral 

adipose tissue; skeletal muscle vs 

liver in a wide BMI range of insulin resistant obese 

patients. Genome-wide screening in patients with 

type 2 diabetes, insulin-resistance-related traits. 

We will continue with the identification of new loci for 

glycaemia, analysis of genome association studies for 

fasting glucose, fasting insulin and indices of beta-cell 

function, and insulin resistance in non-diabetic patients. 

The impact of overnutrition, diabetes-obesity and undernutrition, 

on the regulation of energy homeostasis 

in the central nervous system. From animal models to 

humans. 

Publications 


González-Sánchez JL, Zabena C, Martínez-Larrad MT, 

Martínez-Calatrava MJ, Pérez-Barba M, Serrano-Ríos 

M. Variant rs9939609 in the FTO gene is associated 

with obesity in an adult population from Spain. Clin 

Endocrinol (Oxf), 70, 390-393 (2009) 

Tellechea ML, Aranguren F, Martínez-Larrad MT, 

Serrano-Ríos M, Taverna MJ, Frechtel GD. Ability of lipid 

accumulation product to identify metabolic syndrome 

in healthy men from Buenos Aires. Diabetes Care, 32, 

e85 (2009) 

Zabena C, González-Sánchez JL, Martínez-Larrad 

MT, Torres-García A, Alvarez-Fernández-Represa J, 

Corbatón-Anchuelo A, Pérez-Barba M, Serrano-Ríos M. 

The FTO obesity gene. Genotyping and gene expression 

analysis in morbidly obese patients. Obes Surg, 19, 87- 


Book chapter 

Serrano Ríos M, Riviriego J, Gutierrez-Fuentes 

JA. «Classification of Diabetes Mellitus: Criteria for 

Diagnosis», in Type 2 Diabetes Mellitus. Elsevier, 1-23 










The impact of overnutrition, diabetes-obesity, and undernutrition 



humans 

IODURE: 2009-2010 

Principal Investigators: Manuel Serrano Ríos, Carmen 

Álvarez, Enrique Blázquez, Deborah Burks, Mario 

Vallejo 


International project 

Nutritional Primary Prevention of Type1 Diabetes in 

Children (TRIG) 

NIH, QLK1-CT-2002-00372: 2002-2012 

Principal Investigator: Manuel Serrano Ríos 

Epidemiology genetics studies: The search of new 

genes relevant to obesity-DM2 

MAGIC Study (Meta-Analysis of Glucose and Insulin 

Related Traits Consortium): 2008-In progress 


Project coordinator: José Carlos Flórez, Diabetes Unit 

Center for Human Genetic Research, Massachusetts 

General Hospital 

Private funds 

Morbi-Mortabilidad y Caracterización Genética en el 

ámbito Rural y Urbano de la Provincia de Segovia 

Fundación Mutua Madrileña, FMM08: 2008-2009 


Analysis of the change in the distribution of fat corporal 

88 CibeRdem

and the relation with adipokine levels in patients with 

HIV in retroviral treatment 

Fipse, 236697/07/07: 2007-2010 

Principal Investigators: Vicente Estrada, Manuel Serrano 

Ríos 

Metabolic syndrome, genes, inflammation markers 

Lilly SA: 2006-2010 


Metabolic syndrome and obesity in children 

DANONE: 2007-2009 


Estudio Genómico y Proteómico del Tejido Adiposo en 

Patologías relacionadas con Síndrome Metabólico 

Fundación Mutua Madrileña, FMM06: 2006-2009 


Disposición de Muestras de ADN de Pacientes 

Diagnosticados 



Genetics studies on the Metabolic Syndrome and C-V 

disease 

NEOCODEX: 2004-In progress 


Project coordinator: Agustín Ruiz 

Awards 

«Miembro Honorario Extranjero», Academia Nacional 

de Medicina de Argentina (2009) 

Awardee: Manuel Serrano Ríos ■ 

Fat tissue in morbid obesity: From Histology to Gene Expression, Proteomics and Lipidomics. 


89

Diabetes and Metabolism Research Group 

Institut de Recerca Hospital Universitari Vall d’Hebron, Barcelona 

www.ir.vhebron.net 

Principal Investigator Rafael Simó Associate researcher Cristina Hernández, Albert Lecube, Jordi 

Mesa Postdoctoral fellow Marta García-Ramírez, David Martínez-Selva Research assistant Lidia 

Corraliza PhD student Anna Barbosa, Marta Villarroel Lab technician Lorena Ramos 

Keywords 

Clinical diabetes. Lipid metabolism. Metabolic syndrome. 

Retinopathy. Weight regulation and obesity. 


The Diabetes and Metabolism Research Group has 

been recognized as a consolidated group by the 

Generalitat de Catalunya, as well as a group of excellence 

by the ANEP. 

Apart from belonging to CIBERDEM, our group is associated 

with the cardiovascular disease network (RECAVA). 

Our research is addressed to the pathophysiology of 

diabetic retinopathy and obesity with the final goal of 

discovering new therapeutic targets. Our combination of 

basic and clinical research is important not only in obtaining 

relevant results, but also in facilitating the rapid 

transference of these results to clinical practice. 


The physiopathology of diabetic retinopathy - a new 

approach using integrated biological systems - this is 

our main area of research. 

Insulin resistance and obesity - new pathogenic candidates 

and the study of comorbidities - we are engaged 

with other CIBERDEM groups in two coordinated projects 

for the development of this line of research. 

Endothelial dysfunction, dyslipidaemia and cardiovascular 

disease in type 2 diabetes - this field of research 

will become more important as a consequence of our 

association with RECAVA. 


Our main area of expertise is diabetic retinopathy 

(DR). In fact, we are recognized as a top research 

group in this field. Our second area of 

expertise is the «non classical» risk factors for 

cardiovascular disease. The line devoted to insulin 

resistance and obesity is an emerging one, 

but we have already been able to discover a new 

pathogenic agent in obesity (ZAG), which merited 

an editorial in JCEM (Flik G. ZigZAGing through 

Fat Stores. J Clin Endocr Metab, 94, 4668-4670, 

2009). 

90 CibeRdem


In the context of our research in DR our main achievements 

in 2009 have been the identification of the downregulation 

of the interphotoreceptor retinoid-binding 

protein (IRBP) in the early stages of DR (Diabetologia, 

52, 2633-2641, 2009), and the publication of a review 

article entitled «Advances in the medical treatment of 

diabetic retinopathy» (Diabetes Care, 32,1556-1562, 

2009). It is also worthy of mention that we have been 

the first to describe diabetes as a cause of nephrogenic 

diabetes insipidus (J Clin Endocr Metab, 94, 2060- 

2065, 2009). 

As regards our research line focusing on obesity, we 

have found a new candidate (ZAG) involved in obesity 

(J Clin Endocr Metab, 94, 4499-4507, 2009). In addition, 

we have investigated the sleep disorders and impaired 

pulmonary function associated with obesity and 

diabetes. 


Our future challenges in the field of DR will be threefold: 

to identify the mechanisms that trigger neurodegeneration 

and its consequences in the early stages of 

diabetic retinopathy through the use of integrated systems 

biology; to determine the molecular mechanisms 

involved in blood-retinal barrier disruption and evaluate 

potential new drugs for the treatment of diabetic macular 

oedema; and to explore the proteomic and metabonomic 

profile of the vitreous fluid of diabetic patients 

vs. non diabetic patients. 

In the field of obesity research we are exploring, by 

means of the proteomic analysis of cerebrospinal fluid, 

new regulators of food intake. In addition, a project to 

determine the influence of SHBG/androgens on fat distribution 

and the incidence of diabetes has also been 

initiated (CP08/00058 and PS09/00144). Finally, we are 

engaged in four CIBERDEM projects (see Research 

networks and grants). 

As regards endothelial dysfunction and cardiovascular 

disease in type 2 diabetic patients, we are testing new 

methods of evaluating endothelial damage and the 

prevalence of and the main factors accounting for true 

silent ischaemia. 

Publications 


García-Arumí J, Fonollosa A, Macià C, Hernandez C, 

Martinez-Castillo V, Boixadera A, Zapata MA, Simo 

R. Vitreous levels of erythropoietin in patients with 

macular oedema secondary to retinal vein occlusions: 

a comparative study with diabetic macular oedema. 

Eye (Lond), 23, 1066-1071 (2009) 

Garcia-Ramírez M, Hernández C, Villarroel M, Canals F, 

Alonso MA, Fortuny R, Masmiquel L, Navarro A, García- 

Arumí J, Simó R. Interphotoreceptor retinoid-binding 

protein (IRBP) is downregulated at early stages of diabetic 

retinopathy. Diabetologia, 52, 2633-2641 (2009) 

Hernández C, Rodríguez B, Losada E, Corraliza L, 

García-Ramírez M, Simó R. Normoalbuminuric type 1 

diabetic patients with retinopathy have an impaired tubular 

response to desmopressin: its relationship with 

plasma endothelin-1. J Clin Endocrinol Metab, 94, 

2060-2065 (2009) 

Kazda C, Gallwitz B, Simó R, Guzmán JR, Kraus P, 

Nicolay C, Rose L, Schernthaner G. The European 

Exenatide study of long-term exenatide vs. glimepiride 

for type 2 diabetes: rationale and patient characteristics. 

Diabetes Obes Metab, 11, 1131-1137 


Miranda M, Ceperuelo-Mallafré V, Lecube A, Hernandez 

C, Chacon MR, Fort JM, Gallart L, Baena-Fustegueras 

JA, Simó R, Vendrell J. Gene expression of paired abdominal 

adipose AQP7 and liver AQP9 in patients with 

morbid obesity: relationship with glucose abnormalities. 

Metabolism, 58, 1762-1768 (2009) 

Pardina E, Baena-Fustegueras JA, Catalán R, Galard 

R, Lecube A, Fort JM, Allende H, Vargas V, Peinado- 

Onsurbe J. Increased expression and activity of hepatic 

lipase in the liver of morbidly obese adult patients 

in relation to lipid content. Obes Surg, 19, 894- 


Pardina E, Baena-Fustegueras JA, Llamas R, Catalán 

R, Galard R, Lecube A, Fort JM, Llobera M, Allende 

H, Vargas V, Peinado-Onsurbe J. Lipoprotein lipase expression 

in livers of morbidly obese patients could be 

responsible for liver steatosis. Obes Surg, 19, 608-616 


Pardina E, Lecube A, Llamas R, Catalán R, Galard 

R, Fort JM, Allende H, Vargas V, Baena-Fustegueras 

JA, Peinado-Onsurbe J. Lipoprotein lipase but not hormone-sensitive 

lipase activities achieve normality after 

surgically induced weight loss in morbidly obese patients. 



91

Pardina E, López-Tejero MD, Llamas R, Catalán R, 

Galard R, Allende H, Vargas V, Lecube A, Fort JM, 

Baena-Fustegueras JA, Peinado-Onsurbe J. Ghrelin 

and apolipoprotein AIV levels show opposite trends to 

leptin levels during weight loss in morbidly obese patients. 


Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, 

Antic S, Zdravkovic M, Ravn GM, Simó R; Liraglutide 

Effect and Action in Diabetes 5 (LEAD-5) met+SU 

Study Group. Liraglutide vs insulin glargine and placebo 

in combination with metformin and sulfonylurea 

therapy in type 2 diabetes mellitus (LEAD-5 met+SU): 

a randomised controlled trial. Diabetologia, 52, 2046- 


Selva DM, Lecube A, Hernández C, Baena JA, Fort JM, 

Simó R. Lower zinc-alpha2-glycoprotein production by 

adipose tissue and liver in obese patients unrelated to 

insulin resistance. J Clin Endocrinol Metab, 94, 4499- 


Simó R, García-Ramírez M, Higuera M, Hernández 

C. Apolipoprotein A1 is overexpressed in the retina of 

diabetic patients. Am J Ophthalmol, 147, 319-325.e1 


Villarroel M, García-Ramírez M, Corraliza L, Hernández 

C, Simó R. Effects of high glucose concentration on the 

barrier function and the expression of tight junction proteins 

in human retinal pigment epithelial cells. Exp Eye 


Review 

Simó R, Hernández C. Advances in the medical treatment 

of diabetic retinopathy. Diabetes Care, 32,1556- 


Lecube A, Hernández C, Simó R. Glucose abnormalities 

in non-alcoholic fatty liver disease and 

chronic hepatitis C virus infection: the role of iron 

overload. Diabetes Metab Res Rev, 25, 403-410 







weight loss 




J Vendrell 




mellitus 


Principal Investigators: Joan J Guinovart, Ramon 

Gomis, Rafael Simó 




















diabética incipiente. Estudio de los mecanismos implicados 

a través de un abordaje integrado de biología de 

sistemas 

Ministerio de Ciencia e Innovación, SAF 2009-07408: 



Associate investigator: Miguel Ángel Rodríguez 

Sex hormone-binding globulin (SHBG): identificación 

de los mecanismos moleculares que regulan 

su expresión y papel en la distribución de la grasa 

corporal y en el desarrollo de la diabetes mellitus 

(DM) tipo2 

Instituto de Salud Carlos III, Programa Miguel Servet, 

Fondo de Investigación Sanitaria, CP08/00058: 


Principal Investigator: David M Selva 

92 CibeRdem

Papel de la Sex hormone-binding globulin (SHBG) 

y de los esteroides sexuales en la distribución de la 

grasa corporal y en la aparición de la diabetes mellitus 

tipo2 

Fondo de Investigación Sanitaria (FIS), PS09/00144: 


Principal Investigator: David M Selva 

Mediadores patogénicos del edema macular diabético: 

exploración de nuevos candidatos mediante análisis 

proteómico en humor vítreo y cultivos celulares 

Ministerio de Ciencia e Innovación, SAF 2006-05284: 

2006-2009 


Síndrome de apneas-hipopneas del sueño en mujeres 

premenopáusicas con obesidad mórbida incluidas en 

un programa de cirugía bariátrica. Influencia sobre los 

factores de riesgo cardiovascular: activación simpática, 

inflamación y resistencia a la insulina 


Sanitaria, PI060476: 2006-2009 

Principal Investigator: Albert Lecube 


Suport a Grups de Recerca 

Generalitat de Catalunya, AGAUR, 2005SGR 00030: 



Private funds 


diabética incipiente 

Fundación de la Sociedad Española de Endocrinología 

y Nutrición, Beca Novo Nordisk: 2009-2010 

Principal Investigator: Cristina Hernández 

Estudio del efecto neuroprotector del fenofibrato y candesartan 

en la retinopatía diabética 

Fundación de la Sociedad Española de Endocrinología 

y Nutrición, Beca Sanofi-Aventis: 2009-2010 


Efecto del fenofibrato sobre la permeabilidad de la barrera 

retiniana externa en cultivos de células de epitelio 

pigmentario de retina 

Solvay Pharma SA: 2009-2010 


Desarrollo de variantes moleculares y análogos de 

somatostatina con potencial aplicación en retinopatía 

diabética y otras enfermedades oculares 

BCN Peptides SA: 2008-2009 


Estudio de la fisiopatología de la retinopatía diabética 

Novo Nordisk Pharma SA: 2007-2010 


Identificación mediante análisis proteómico del humor 

vítreo de nuevas dianas terapéuticas en la retinopatía 

diabética proliferativa y en el edema macular 

diabético 

Fundación para la Diabetes, Beca Rodríguez Miñón: 




DEFEND-1: Durable-Response Therapy Evaluation for 

Early- or New-Onset Type 1 Diabetes. TRX4_DM_007_ 

EU_08. Phase III 

Constella Group SA: 2009-2011 

Name of the participants: Cristina Hernández, Rafael 

Simó (researchers) 

Estudio multicéntrico, de 24 semanas seguido por una 

extensión, aleatorizado, doble ciego controlado con 

placebo y de grupos paralelos, para evaluar la eficacia 

y seguridad de AVE0010 añadido a metformina en pacientes 

con diabetes tipo 2 no controlados adecuadamente 

con metformina. EFC6014. Phase III 


Name of the participants: Jordi Mesa, Albert Lecube 

(researchers) 

A 16 week randomised, open labelled, 3-armed, parallel 

group, treta-to-target trial comparing SIAM A and B 

with each other and with NovoMix 30, all alter twice daily 

injections (BID) and in combination with metformin in 

subjects with type 2 diabetes. NN5401-1792. Phase III 

Novo Nordisk Pharma SA: 2008-2009 

Name of the participants: Rafael Simó (steering committee 

member), Albert Lecube (researcher) 

Tratamiento comparativo a largo plazo con exenatida 

y glimepirida en pacientes con diabetes de tipo 2 previamente 

tratados con metformina. H80-EW-GWBE. 

Phase III 

Lilly SA: 2007-2009 

Name of the participants: Rafael Simó (steering committee 

member), Albert Lecube (researcher) 


93


Complicaciones crónicas de la diabetes mellitus I. Retinopatía 

y otros problemas oculares. Manual del Residente 

Euromedice Ediciones Médicas (2009) 

Sociedad Española de Endocrinología y Nutrición 

Authors: Rafael Simó, Cristina Hernández 

Patents 


Formulación tópica oftálmica de péptidos 

Patent application number: P200931242 

Inventors: R Simó, C Hernández, J Fernández, M Gómez, 

R Jordana, J Farrera, B Bonsati 

Institut de Recerca Hospital Universitari Vall d’Hebron 

and BCN Peptides SA (2009) 

Awards 

«Premio de Investigación Clínica Junior», Sociedad 

Española de Diabetes (2009) 

Awardee: Albert Lecube ■ 

Evidence for tight junctions and polarity in ARPE-19 monolayers. 

(A) Expression of ZO-1, (C) occludin, (E) claudin-1 and (G) Na+/ 

K+ ATPase. Confocal vertical (X-Z) sections showing polarization of 

ARPE-19 cells. (H) Immunofluorescence of the apical marker enzyme 

Na+/K+ ATPase and (B) ZO-1, (D) occludin and (F) claudin-1 

staining showing apical localization of tight junctions. Bar: 10µm. 

94 CibeRdem

Endocrinology and Nutrition Service 

Hospital Regional Universitario Carlos Haya, Málaga 

www.carloshaya.net 

www.imabis.org 

Principal Investigator Federico Soriguer Associate researcher María Cruz Almaraz, Isabel Esteva de 

Antonio, Juan Miguel Gómez, María Stella González, Sonsoles Morcillo, Gabriel Olveira, Gemma Rojo, María 

Soledad Ruiz de Adana, Sergio Valdés Postdoctoral fellow Eva García Research assistant Isabel Cardona 

PhD student Carolina Gutiérrez, Juan José Haro, Elehazara Rubio Lab technician María de Haro-Martín, 

Sara García, Francisca Linares, Gracia María Martín, Nuria Porras Administrative staff Patricia González 

Keywords 

Epidemiology. Insulin therapy. Metabolic syndrome. 

Prediction/prevention of type 2 diabetes. Weight regulation 

and obesity. 


We are a research group with epidemiological, clinical 

and experimental projects whose ultimate purpose is the 

study of nature-nurture relationships in the explanation of 

metabolic phenotypes such as diabetes. The methodology 

is an ongoing dialogue between clinical, epidemiological 

and experimental observations. The group operates from 

a holistic conception of human biology and from, on the 

one hand, the knowledge of the natural history of people’s 

health and on the other hand, clinical intervention for the 

prevention of metabolic risk factors and type 2 diabetes. 


The biomolecular epidemiology of diabetes, obesity 

and metabolic syndrome (Pizarra Study, Egabro Study, 

di@bet.es Study, di@bet.an Study). 

The study of insulin resistance in patients with extreme 

obesity undergoing bariatric surgery. 

Fatty acids, insulin resistance and adipocyte 

metabolism. 

New technologies applied to the treatment of type 1 

diabetes. 

Pancreas islet transplantation in type 1 diabetes. 


Epidemiological analysis techniques. 

Biochemical analysis (gas chromatography, immunoassays). 

Genetic analysis and genetic expression (Biomolecular 

techniques). 

Adipocyte culture. 

New technologies applied to the treatment of type 1 

diabetes. 


From the Pizarra Study we have shown that the increase 

in the prevalence of obesity in the free-living 


95

population is associated with the type of fatty acids in 

the diet and that Trp64Arg polymorphism of the ADRB3 

gene predicted the risk of developing hyperuricaemia in 

this adult population. 

In this population, women with hypertension had lower 

levels of IgG anti-oxidized LDL antibodies than normotensive 

women and type 2 diabetes mellitus and other 

cardiovascular risk factors are no more common during 

the menopause. 

We have shown from extreme obesity studies that apelin 

plays a role in the pathogenesis of diabetes and 

that the changes in the serum composition of free fatty 

acids during an intravenous glucose tolerance test are 

characteristic of diabetes and other alterations. 


To finish the fourth phase of the Pizarra study. 

To develop the Egabro study (DM2 primary prevention). 

To finish the di@bet.es Study. 

To continue insulin-resistance studies in severely obese 

subjects. 

To continue fatty-acid metabolism studies in culture 

adipocytes. 

To study the relationship between milk beta2globulin 

Ab and GADA in the general population. 

Publications 


Garrido-Sánchez L, García-Fuentes E, Cardona F, 

Rojo-Martínez G, Soriguer F, Tinahones FJ. Antioxidized 

LDL antibody levels are reduced in women 

with hypertension. Eur J Clin Invest, 39, 800-806 (2009) 

Soriguer F, Almaraz MC, Ruiz-de-Adana MS, Esteva 

I, Linares F, García-Almeida JM, Morcillo S, García- 

Escobar E, Olveira-Fuster G, Rojo-Martínez G. 

Incidence of obesity is lower in persons who consume 

olive oil. Eur J Clin Nutr, 63, 1371-1374 (2009) 

Soriguer F, García-Serrano S, García-Almeida JM, 

Garrido-Sánchez L, García-Arnés J, Tinahones FJ, 

Cardona I, Rivas-Marín J, Gallego-Perales JL, García- 

Fuentes E. Changes in the serum composition of freefatty 

acids during an intravenous glucose tolerance 

test. Obesity (Silver Spring), 17, 10-15 (2009) 

Soriguer F, Garrido-Sanchez L, Garcia-Serrano S, 

Garcia-Almeida JM, Garcia-Arnes J, Tinahones FJ, 

Garcia-Fuentes E. Apelin levels are increased in 

morbidly obese subjects with type 2 diabetes mellitus. 


Soriguer F, Morcillo S, Hernando V, Valdés S, Ruiz de 

Adana MS, Olveira G, Fuentes EG, González I, Tapia 

MJ, Esteva I, Rojo-Martínez G. Type 2 diabetes mellitus 

and other cardiovascular risk factors are no 

more common during menopause: longitudinal study. 

Menopause, 16, 817-821 (2009) 

Tinahones FJ, Murri-Pierri M, Garrido-Sánchez L, 

García-Almeida JM, García-Serrano S, García-Arnés 

J, García-Fuentes E. Oxidative stress in severely obese 

persons is greater in those with insulin resistance. 











REPROBESITY: Search For New Therapeutic Agents 

Against Complicated Obesity By Reprofiling Existing 

Drugs 

European Union, Seventh Framework Programme, 

FP7-HEALTH-2007-B: 2009-2012 

Associate investigator: Federico Soriguer 


Prevención de la Diabetes mellitus tipo 2. Estudio 

Egabro-Pizarra 

Instituto de Salud Carlos III, PI08/1592: 2009-2011 

Principal Investigator: Gemma Rojo 

Estudio comparativo de terapia con infusores subcutáneos 

de insulina(isci) versus sistema integrado isci y 

sensor continuo de glucosa con transmisión a tiempo 

real por ondas.Impacto sobre variables metabólicas , 

psicológicas y de calidad de vida 

Instituto de Salud Carlos III, PI 07/90330: 2008-2010 

Principal Investigator: María Soledad Ruiz de Adana 

Estudio de la variabilidad genética de la delta-9-desaturasa 

en la población general y su asociación con la obesidad 

Instituto de Salud Carlos III, CP07/00187: 2007-2010 

96 CibeRdem

Principal Investigator: Juan Miguel Gómez Zumaquero 

Tamaño y número de los adipositos en la infancia. 

Influencia de los ácidos grasos de la dieta sobre la dotación 

adipocitaria 

Instituto de Salud Carlos III, CP06/00133: 2007-2010 



Papel del tejido adiposo y las adipoquinas en el desarrollo 

de Diabetes tipo 2. Un estudio de cohortes 

poblacional 

Consejería de Salud Junta de Andalucía, 0189/2008: 

2008-2010 


Prevención de la Diabetes mellitus tipo 2. Estudio 

Egabro 


2008-2010 

Principal Investigator: Federico Soriguer 

Genes candidatos y Dieta Mediterránea: prevalencia 

de diabetes tipo 2 en Andalucía. Estudio Diabetan 


2008-2010 

Principal Investigator: Sonsoles Morcillo 

Estudio del dimorfismo sexual metabólico y hormonal 

en personas transexuales durante el proceso de reasignación 

de sexo 


2008-2010 

Principal Investigator: Isabel Esteva de Antonio 

Genoma España: 2009-2012 



APIDR_C_02083. Efecto de la insulina glulisina en 

comparación con la insulina aspart y la insulina lispro 

cuando se administran mediante Infusión Subcutánea 

Continua de Insulina (ISCI) sobre parámetros específicos 

de la bomba en pacientes con Diabetes Mellitus 

de tipo 1 


BIASP-1731. Comparación multinacional, abierta, 

aleatorizada, de grupos paralelos, con un periodo de 

prueba de 4 semanas y 26 semanas de tratamiento 

hasta conseguir el objetivo, de insulina aspart bifásica 

30 una vez al día frente a insulina glargina una vez 

al día, ambas en combinación con metformina y con 

glimepirida, en pacientes con diabetes tipo 2 que no 

han recibido tratamiento con insulina 

Novo Nordisk Pharma: 2007-2009 

CLAF237A2308. Estudio multicéntrico, aleatoriazdo, 

doble ciego controlado con fármaco activo para comparar 

el efecto del tratamiento a largo plazo (hasta 5 

años) de 50 mg LAF237 bid con glimepirida adosis de 

hasta 6mg/dia como terapia añadida en pacientes con 

diabetes Tipo 2 que no esten controlados adecuadamente 

con metformina en monoterapia 

Novartis: 2005-2010 ■ 

Prevalencia de Diabetes tipo 2, obesidad y Síndrome 

metabólico en Andalucía. Estudio Diabetan 


2008-2010 


Obesidad, Síndrome Metabólico y Dieta Mediterránea. 

Una hipótesis relacionada con el aceite de oliva 




Private funds 

Proyecto de puesta a disposición de muestras de 

ADN de pacientes diagnosticados de una enfermedad 

metabólica en la población española 

Gas chromatography determination of tissue and serum fatty 

acid composition. 


97

Transcription factors in insulin resistance and 

the metabolic syndrome 

Unitat de Farmacologia, Facultat de Farmàcia, Universitat de Barcelona 

www.ub.edu 

Principal Investigator Manuel Vázquez-Carrera Associate researcher Marta Alegret, Juan 

Carlos Laguna, Manuel Merlos, Núria Roglans, Rosa María Sánchez Postdoctoral fellow Xavier 

Palomer PhD student Emma Barroso, Teresa Coll, Jordi Pou, Alba Rebollo, Lucía Serrano, Laia Vilà 

Lab technician David Álvarez-Guardia 

Keywords 

Insulin sensitivity and resistance. Lipid metabolism. Lipids, 

lipoproteins. Metabolic syndrome. Transcription factors. 


Over the last decade an abundance of evidence has 

emerged demonstrating a close link between a state 

of chronic low-level inflammation and obesity, insulin 

resistance and type 2 diabetes mellitus. The aim of our 

research group is to identify the molecular mechanisms 

that link inflammation and the development of insulin 

resistance in several cell types (skeletal muscle cells, 

adipocytes, cardiomyocytes and hepatocytes) in in vitro 

and in vivo models of insulin resistance and to evaluate 

the effects of new drugs on these pathways. 

agonists prevent inflammation and insulin resistance; 

studying how monounsaturated fatty acids prevent saturated 

fatty-acid-induced insulin resistance; evaluating 

the mechanisms through which statins may prevent 

the development of metabolic syndrome and cardiac 

hypertrophy; and studying the molecular mechanisms 

responsible for the development of dyslipidaemia and 

leptin resistance in an animal model of metabolic syndrome 

(the fructose-fed rat). 


Cellular and animal models of insulin resistance and 

metabolic syndrome. 

Nuclear receptors and transcription factors. 

Cellular and animal models of cardiac hypertrophy. 


Our main research topic is the study of the molecular 

mechanisms involved in the link between inflammation 

and insulin resistance. Specifically we are interested in: 

evaluating the molecular mechanisms by which PPAR 


Atorvastatin prevents the activation of the carbohydrate 

response element binding protein (ChREBP) in the liver 

of the fructose-fed rat, an animal model of metabolic 

syndrome, through the activation of protein kinase A. 

98 CibeRdem

This mechanism may contribute to the hypotriglyceridaemic 

effect of atorvastatin. 

TNF-alpha reduces PGC-1alpha expression through 

NF-κB and p38 MAPK leading to increased glucose oxidation 

in a human cardiac cell model. This mechanism 

can contribute to cardiac dysfunction and heart failure in 

metabolic disorders with an inflammatory background. 


To evaluate the mechanisms by which PPAR-beta/delta 

activation in vivo prevents the development of insulin 

resistance and inflammation in the liver, white adipose 

tissue, heart and skeletal muscle. 

To assess whether PPAR-beta/delta activation prevents 

the downregulation of PGC-1alpha in a human cardiac 

cell model and in a transgenic mouse model overexpressing 

TNF-alpha in the heart. 

To assess the mechanisms involved in the development 

of leptin resistance in an animal model of metabolic 

syndrome, the fructose-fed rat. 

Publications 


Palomer X, Alvarez-Guardia D, Rodríguez-Calvo R, Coll 

T, Laguna JC, Davidson MM, Chan TO, Feldman AM, 

Vázquez-Carrera M. TNF-alpha reduces PGC-1alpha 

expression through NF-kappaB and p38 MAPK leading 

to increased glucose oxidation in a human cardiac cell 

model. Cardiovasc Res, 81, 703-712 (2009) 

Rodríguez-Calvo R, Barroso E, Serrano L, Coll T, 

Sánchez RM, Merlos M, Palomer X, Laguna JC, 

Vázquez-Carrera M. Atorvastatin prevents carbohydrate 

response element binding protein activation 

in the fructose-fed rat by activating protein kinase A. 

Hepatology, 49, 106-115 (2009) 

Review 

Coll T, Rodríguez-Calvo R, Barroso E, Serrano L, Eyre 

E, Palomer X, Vázquez-Carrera M. Peroxisome proliferator-activated 

receptor (PPAR) beta/delta: a new potential 

therapeutic target for the treatment of metabolic 

syndrome. Curr Mol Pharmacol, 2, 46-55 (2009) 




diabetes 






Normal and hypertrophied cardiomyocytes. 


99











Vías moleculares que conectan la inflamación con la resistencia 

a la insulina y la hipertrofia cardiaca. Estudio 

de los efectos de los ligandos de PPAR-beta/delta, el 

ácido oleico y las estatinas en modelos celulares y animales 

de resistencia a la insulina, síndrome metabólico 

e hipertrofia cardíaca 

Ministerio de Ciencia e Innovación, SAF2009-06939: 


Principal Investigator: Manuel Vázquez-Carrera 

Papel de la vía de las MAPK/LKB1/AMPK en la hipertrigliceridemia 

inducida por la ingesta de fructosa en rata: 

modulación farmacológica 

Ministerio de Sanidad y Consumo, PI070875: 



Project coordinator: Núria Roglans 

Desarrollo de plataformas tecnológicas comunes dirigidas 

a la identificación de candidatos a desarrollo preclínico 

en varias áreas terapéuticas Genius Pharma AIE 

Ministerio de Industria: 2007-2009 


Project coordinators: Manuel Vázquez-Carrera, Juan C 

Laguna 

Inflamación, diabetes e hipertrofia cardíaca. Estudio 

del efecto de fármacos inhibidores del factor transcripción 

NF-KB en modelos celulares y animales de resistencia 

a la insulina e hipertrofia cardíaca 



Principal Investigator: Manuel Vázquez-Carrera ■ 

100 CibeRdem

Diabetes and Metabolic Associated Diseases 

Research Group 

Institut d’Investigació Sanitària Pere Virgili, Hospital Universitari de Tarragona Joan XXIII 

www.iispv.cat 

Principal Investigator Joan J Vendrell Associate researcher Xavier Escoté, Luís Gallart, Antonio 

García-España, Cristina Gutiérrez, Anna Megía, Matilde Rodríguez, Inmaculada Simón Postdoctoral 

fellow Mercedes Miranda Research assistant María Victoria Ceperuelo Lab technician Miriam 

Campos, Elsa Maymó, Gisela Pachón, Marta Sanjuán Administrative staff María de la Coba 

Keywords 

Insulin sensitivity and resistance. Metabolic syndrome. 

Prediction/prevention of type 2 diabetes. Pregnancy. 

Weight regulation and obesity. 


Type 2 diabetes (DM2) and obesity are both associated 

with a local and systemic chronic «low inflammatory 

degree». The emerging role of the adipose tissue as 

a veritable endocrine organ has provided new insights 

into the mechanisms of insulin resistance linking type 

2 diabetes and obesity. Specific adipokines, inflammatory 

proteins and modifications in the innate immune 

system establish a fragile equilibrium that may account 

for many pathogenic processes in adipocyte biology 

contributing to these metabolic diseases. 


Inflammatory mechanisms in type 2 diabetes and insulin 

resistance (chronic activation of the immune system). 

Genetic susceptibility markers in diabetes (genetic and 

environmental interaction in diabetes; DNA biobank). 

Adipose cell biology - regulatory mechanisms of different 

adipose tissue cell types. Mesenchymal stem-cell 

biology (genes involved in adipose cell differentiation 

- paracrine/endocrine analysis of adipose tissue inflammatory 

mechanisms in obesity and diabetes). 


Phenotyping of type 2 diabetes and obese cohorts. 

Adipose tissue handling (cell fractioning and separation, 

primary and adipocyte cell-line culture). 

Gene and protein expression analysis. 

Quantification of circulating inflammatory and anti-inflammatory 

proteins. 

Mesenchymal stem cell handling. In vivo insulin sensitivity 

analysis (minimal model technique). 

Indirect calorimetry. 


The recruitment of type 2 diabetic, obese and gestational 

diabetes cohorts. New insights into adipose 


101

tissue gene expression profile in lean, obese, morbidly 

obese and type 2 diabetic patients. Adipose tissue fractioning 

(adipocytes and stromo-vascular tissue) from 

lean and obese cohorts. Optimization of a cell line culture 

to study inflammatory and adipogenic stimulus. 

The relationship of new inflammatory proteins with insulin-resistance 

and metabolic abnormalities. Starting 

adipose tissue stem cell differentiation. 


Massive analysis of genetic expression in isolated cells 

from several subgroups of obese and diabetic patients. 

The design of protein expression projects on the same 

cell groups where genetic expression has been studied. 

Studies on mesenchymal cells isolated from the stromovascular 

fraction of the adipose tissue from obese 

and diabetic patients will be started. Insulin resistant 

adipocyte simulation studies will be also performed and 

their response to new inflammatory and anti-inflammatory 

stimuli will be continued. 

Publications 


Broch M, Auguet MT, Ramírez R, Olona M, Aguilar C, 

Megia A, Alcaide MJ, Pastor R, Martínez S, Caubet E, 

Garcia-España A, Richart C. Parallel downregulation 

of retinol-binding protein-4 and adiponectin expression 

in subcutaneous adipose tissue of non-morbidly obese 

subjects. Eur J Endocrinol, 161, 87-94 (2009) 

Caixàs A, Tirado R, Vendrell J, Gallart L, Megía A, 

Simón I, Llauradó G, González-Clemente JM, Giménez- 

Palop O. Plasma visfatin concentrations increase in 

both hyper and hypothyroid subjects after normalization 

of thyroid function and are not related to insulin resistance, 

anthropometric or inflammatory parameters. 

Clin Endocrinol (Oxf), 71, 733-738 (2009) 

Ceperuelo-Mallafré V, Näf S, Escoté X, Caubet E, 

Gomez JM, Miranda M, Chacon MR, Gonzalez- 

Clemente JM, Gallart L, Gutierrez C, Vendrell J. 

Circulating and adipose tissue gene expression of zincalpha2-glycoprotein 

in obesity: its relationship with adipokine 

and lipolytic gene markers in subcutaneous and 

visceral fat. J Clin Endocrinol Metab, 94, 5062-5069 


Chacón MR, Ceperuelo-Mallafré V, Maymó-Masip E, 

Mateo-Sanz JM, Arola L, Guitiérrez C, Fernandez-Real 

JM, Ardèvol A, Simón I, Vendrell J. Grape-seed procyanidins 

modulate inflammation on human differentiated 

adipocytes in vitro. Cytokine, 47, 137-142 (2009) 

Fernández-Real JM, Handberg A, Ortega F, Højlund K, 

Vendrell J, Ricart W. Circulating soluble CD36 is a novel 

marker of liver injury in subjects with altered glucose 

tolerance. J Nutr Biochem, 20, 477-484 (2009) 

Gómez JM, Vilarrasa N, Masdevall C, Pujol J, Solano 

E, Soler J, Elio I, Gallart L, Vendrell J. Regulation of 

bone mineral density in morbidly obese women: a 

cross-sectional study in two cohorts before and after 

bypass surgery. Obes Surg, 19, 345-350 (2009) 

Huth C, Illig T, Herder C, Gieger C, Grallert H, Vollmert 

C, Rathmann W, Hamid YH, Pedersen O, Hansen T, 

Thorand B, Meisinger C, Doring A, Klopp N, Gohlke H, 

Lieb W, Hengstenberg C, Lyssenko V, Groop L, Ireland 

H, Stephens JW, Wernstedt Asterholm I, Jansson 

JO, Boeing H, Mohlig M, Stringham HM, Boehnke M, 

Tuomilehto J, Fernandez-Real JM, Lopez-Bermejo A, 

Gallart L, Vendrell J, Humphries SE, Kronenberg F, 

Wichmann HE, Heid IM. Joint analysis of individual 

participants’ data from 17 studies on the association of 

the IL6 variant -174G>C with circulating glucose levels, 

interleukin-6 levels, and body mass index. Ann Med, 

41, 128-138 (2009) 

Miranda M, Ceperuelo-Mallafré V, Lecube A, Hernandez 

C, Chacon MR, Fort JM, Gallart L, Baena-Fustegueras 

JA, Simó R, Vendrell J. Gene expression of paired abdominal 

adipose AQP7 and liver AQP9 in patients with 

morbid obesity: relationship with glucose abnormalities. 

Metabolism, 58, 1762-1768 (2009) 

Simón I, Escoté X, Vilarrasa N, Gómez J, Fernández- 

Real JM, Megía A, Gutiérrez C, Gallart L, Masdevall C, 

Vendrell J. Adipocyte fatty acid-binding protein as a determinant 

of insulin sensitivity in morbid-obese women. 







weight loss 



102 CibeRdem


J Vendrell 












Estudio del efecto de la citocina TWEAK en la insulino 

resistencia del adipocito. Relación de la fracción 

soluble y de su expresión génica con marcadores inflamatorios 

en pacientes obesos con diabetes tipo 2 y 

con diferente grado de insulino resistencia 

Instituto de Salud Carlos III, 08/0733: 2009-2011 

Principal Investigator: Matilde Rodríguez Chacón 

Estudio de la regulación del gen LPIN1 en pacientes 

con obesidad y diabetes mellitus tipo 2. Análisis in vitro 

en adipocitos humanos de su respuesta a diferentes 

estímulos lipolíticos 

Instituto de Salud Carlos III, 08/1195: 2009-2011 

Principal Investigator: Joan J Vendrell 

Estudio del canal de glicerol (acuaporina 7) en la 

regulación coordinada del metabolismo del glicerol 

y de la glucosa en tejido adiposo abdominal 

humano. Disfunción en la obesidad y en la diabetes 

tipo 2 

Instituto de Salud Carlos III, 07/1024: 2008-2010 


Papel pro-inflamatorio de la citocina tweak y de su receptor 

Fn14 sobre adipocitos humanos diferenciados in 

vitro a partir de células madre mesenquimales. Estudio 

de su relación con la resistencia a la insulina y marcadores 

inflamatorios 

Instituto de Salud Carlos III, CP06/00119: 2007-2009 

Principal Investigator: Matilde Rodríguez Chacón 

Adipogenic and osteogenic differentiation of the adipose tissue mesenchymal stem cell. 


103

Private funds 

El papel de la citoquina TWEAK en la diabetes gestacional 

y su relación con otras adipoquinas y la sensibilidad 

a la insulina 

Novo Nordisk Pharma: 2009-2011 


Biology of GLP1 in adipose tissue: Characterization of 

a new insulin-mediated adipose cell proliferation control 

factor and its implications in inflammation and diabetes 

MSD: 2009 


Ampliación del Banco Nacional de ADN. Nodo de 

Enfermedades Metabólicas 




Estudio de fase II, doble ciego, aleatorizado, de grupos 

paralelos, para evaluar la seguridad, eficacia y farmacocinética 

de BI 10773 (1 mg, 5 mg, 10 mg, 25 mg y 

50 mg) administrado una vez al día por vía oral durante 

12 semanas, comparado con placebo y con un 

brazo abierto adicional con sitagliptina, en pacientes 

con Diabetes Mellitus tipo 2 con un control insuficiente 

de la glucemia a pesar del tratamiento con metformina. 

Phase II 

Boehringer Ingelheim: 2009 

Name of the participants: Joan J Vendrell, Anna Megía, 

Inmaculada Simón ■ 

104 CibeRdem

Area 3 

Islet dysfunction, destruction and regeneration 

Autoimmunity 

Impact on the pathogenesis of diabetes

Area 3 of CIBERDEM involves thirteen groups focused on developing new tools and knowledge for the molecular 

diagnosis of beta-cell function and for the cell and gene therapy of diabetes. In 2009, we were pleased to be able 

to welcome a new group led by Anna Novials. 

Following the investigations initiated in the previous year, the role of several hormones and hormone receptors in beta cells 

was investigated. Mouse studies established that beta-cell specific expression of placental lactogen hormone rescued 

diabetes in IRS-2-deficient mice. A complete phenotypic characterization of Alx3 knockout mice was performed in 2009. 

We also studied the function of leptin receptors in alpha cells and the role of the oestrogen receptor beta on insulin 

secretion and beta-cell replication. In addition, the role of the enzyme iduronate sulfatase (IDS), cannabinoid receptors, 

and PPARalpha ligands in alpha and beta cells was studied. The pancreatic presence of TH was demonstrated in early 

stages of mouse embryonic development. Furthermore, one specific pancreatic cell population, named stellate cells, was 

identified; these have the properties of progenitor cells and express and produce insulin. 

In 2009, genetic studies played an important role in this area. Significant advances were reported in monogenic 

forms of diabetes involving HNF1A and PDX-1 gene mutations. Also, mutations in the INS promoter were 

associated with neonatal diabetes and a functional variant in the MHC was found to modulate the risk of T1D. 

TCF7L2, math6 and wnt9a genes were studied and the identification of the transcriptional hierarchy among 

GATA4, FoxA2 and PDX1 transcription factors in the endoderm specification was reported. Lineage tracing studies 

demonstrated that ductal cells do not differentiate to beta cells in adult mice. Of significant value for the network 

was the implementation of high throughput sequencing and microarray technologies to dissect the epigenetic 

mechanisms underlying beta-cell identity. 

Several cell- and gene-therapy approaches to recover beta-cell mass are also being examined. One major 

achievement this year includes the development of feeder-free conditions for the efficient differentiation of hESC to 

definitive endoderm. Additionally, hESC reporter cell lines to monitor the expression of beta-cell markers (e.g. insulin, 

PdX1, IRS-1 and IRS-2) and hepatocyte markers were characterized. In addition, a novel iPS cell line able to express 

eGFP under PDX1 and dsRed-1 under insulin promoter will help to understand beta-cell differentiation pathways. 

We also made innovations in human islet isolation techniques, leading to improved islet quality. Furthermore, three 

diabetes cell-therapy clinical trials were initiated this year. In parallel to cell therapy, novel approaches to increase 

beta-cell mass in vivo by using viral vector-mediated gene transfer are currently being tested. 

In summary, the activities conducted during 2009 proved very successful and have resulted in key developments 

in the beta-cell field. 

Fàtima Bosch 



107

Endocrinology and metabolism 

Departamento de Bioquímica y Biología Molecular II, Facultad de Farmacia, Universidad Complutense de Madrid 

www.ucm.es/info/biomol2 

Principal Investigator Carmen Álvarez Associate researcher Fernando Escrivá, María Ángeles 

Martín Postdoctoral fellow Elisa Fernández PhD student Laura de Miguel, Juan de Toro 

Lab technician Esther Lizárraga 

Keywords 

Beta-cell signal transduction. Insulin action. Insulin sensitivity 

and resistance. Islet development. Pregnancy. 


Nutritional status has an impact on pancreatic islet 

cells and tissue insulin action. Different studies in humans 

and animals have shown that early undernutrition 

alters glucose metabolism and increases the risk 

of developing type 2 diabetes. However, little is known 

about the mechanisms involved in such disturbances. 

We are particularly interested in the molecular alterations 

produced by nutrients in the growth, development 

and death of islet cells and insulin action in the 

brain and liver. 


To analyse the molecular mechanisms which link foetal 

programming and metabolic disorders in adult life; 

in particular to study the effects of nutrients on the development, 

growth and death of pancreatic islet cells 

and the implication of IGFs. 

To study the action of insulin on hormone responses in 

both peripheral and central tissues: the liver, cortex and 

hypothalamus; specifically, an analysis of the amount 

and phosphorylation of proteins in insulin signalling 

both before and after insulin stimulation. 


Animal models of undernutrition and diabetes. Pancreas 

plasticity. Islet cells. IGF-system. Insulin and IGF-1 signalling. 

Apoptosis. The hyperinsulinaemic euglycaemic 

clamp. Immunohistochemistry and morphometry. 


Our results have shown that maternal undernutrition 

partially suppresses the physiological wave of beta-cell 

apoptosis during the neonatal period in Wistar rats; that 

maternal malnutrition ameliorates beta-cell mass in U-GK 

foetuses (a specific pancreatic IGF-2 increase may be 

instrumental in this effect); that undernutrition increases 

the astrocytic glycogen in suckling rats; and that cortical 

108 CibeRdem

p-GSK-3, which regulates glycogen synthesis is also enhanced 

by undernutrition. 


Foetal programming induced by nutrients (over/undernutrition) 

could provoke obesity and diabetes in later 

life. Our aim is to study the molecular mechanisms underlying 

the epigenetic modifications induced by nutrition 

during embryonic endocrine pancreas development 

and also the possible effects of nutrition on central and 

peripheral insulin sensitivity, analysing the hormone 

signalling pathway in regions of the brain involved in 

learning and appetite control, as well as in the liver. 


Mecanismos moleculares implicados en el desarrollo 

y crecimiento de las células beta pancreáticas y en las 

acciones de la insulina en el SNC: estudio en ratas 

subnutridas 

Comunidad Autónoma de Madrid, CCG07-UCM/SAL- 

3004: 2009-2010 

Principal Investigator: Fernando Escrivá ■ 

Publications 


Fernández-Millán E, Gangnerau MN, De Miguel- 

Santos L, Calderari S, Serradas P, Escrivá F, Portha B, 

Alvarez C. Undernutrition of the GK rat during gestation 

improves pancreatic IGF-2 and beta-cell mass in the 

fetuses. Growth Factors, 27, 409-418 (2009) 



The impact of overnutrition, diabetes-obesity and undernutrition 

on the regulation of energy homeostasis in the 

central nervous system. From animal models to humans 



Álvarez, Enrique Blázquez, Deborah Burks, Mario 

Vallejo 


Maternal undernutrition increases pancreatic IGF-2 (A) and partially 

suppresses the physiological wave of beta-cell apoptosis 

during the neonatal period (B), probably through the inhibition of 

glycogen synthase kinase-3 (C). 


Mecanismos moleculares que regulan el crecimiento y 

muerte de las células beta pancreáticas y las acciones 

insulínicas en el SNC: estudio en ratas subnutridas y 

diabéticas 

Ministerio de Ciencia e Innovación, BFU 2008-02930: 


Principal Investigator: Carmen Álvarez 

Programming of beta cell mass Homeostasis in 

Diabetes. Relationship with pancreatic IGFs 

Ministerio de Ciencia e Innovación, HF2007-0076: 


Principal Investigator: Carmen Álvarez 

Project coordinator: Bernard Portha 

The microphotographs show cortical glycogen stained by a PASdimedone 

procedure (A, C). As is known, it is present only in 

astrocytes, neurons being free of this metabolite (B, D). 


109

Brain glucose sensor, satiety control, insulin 

resistance and type 2 diabetes 

Universidad Complutense de Madrid 

www.ucm.es 

Principal Investigator Enrique Blázquez Associate researcher Elvira Álvarez, María Ángeles 

Navas, Isabel Roncero, Juan Miguel Ruiz-Albusac, Esther Velázquez, José Antonio Zueco 

Postdoctoral fellow María del Carmen Sanz PhD student Manuel Álvaro Berbís, Elena María 

Blanco, María Cristina Espinosa, Carmen García, Verónica Hurtado Lab manager Pedro Alberto 

Barrio Lab technician Alberto Crespo 

Keywords 

Genetics type 2 diabetes. Hormone receptors. Incretins. 

Stem cells. Weight regulation and obesity. 


GLPs are important for several biological processes. 

We have reported that GLP-1 reduced glucose metabolism 

in areas involved in food intake, as well as causing 

changes in patients with abnormal feeding behaviour. 

At a cellular level, GLP-1 modulates the cerebral gene 

expression of AMPK and other metabolic sensors. 

GLP-2 activates astrocyte proliferation and here we describe 

a synergistic effect with EGF, PDGF, IGF-I and 

insulin, suggesting new insights into the action of this 

peptide. In hMSC, mouse embryonic stem cells and in 

the early stages of mouse embryos, GLP-1 has proliferative 

and cytoprotective actions, as well as interfering 

with cell differentiation to adipocytes. These findings 

underscore the potential therapeutic role of GLP-1 in 

preventing the adipocyte hyperplasia associated with 

obesity and in the maintenance of hMSC stores. Our 

findings indicate that GK and GKRP are active before 

birth and that they can act as a glucose sensor system. 

Mutations implied in monogenic diabetes have clinical 

interest, but may also be relevant as models of structure 

and function. Thus, the functional characterization 

of MODY 3 mutations has allowed the detection of defects 

in the DNA binding activity, transactivation and 

subcellular location of HNF-1alpha. 


Modifications of cerebral glucose metabolism in pathophysiological 

states related to feeding behaviour (E 

Blázquez, M Serrano Ríos, MA Pozo and JA Zueco). 

The effects of GLP-1 and GLP-2 on genic expression 

and the activities of GK, AMP and PAS kinases in the 

brain (E Álvarez, C Sanz, V Hurtado and E Blanco). 

The effect of GLP-2 on the proliferation of cultured rat 

astrocytes (E Velázquez, E Blázquez and JM Ruiz). 

Signalling and the biological effects of GLP-1 on 

mesenchymal stem cells of human bone marrow and 

mouse embryonic stem cells - its effect on cell differentiation 

(C Sanz, P Barrio, MA Berbís and E Blázquez). 

Molecular diagnosis of monogenic diabetes (MODY) 

110 CibeRdem

and the functional characterization of MODY mutations 

(MA Navas, CM García-Herrero and C Espinosa). 

To carry out a molecular diagnosis of monogenic diabetes 

with special emphasis on the functional characterization 

of these mutations. 


The determination of hormones and growth factors by 

immunoassay. The study of signal transduction pathways. 

The isolation and primary culture of mesenchymal 

stem cells from bone marrow and pancreatic islets. 

Cultures of cell lines and hypothalamic organotypic 

slices. Molecular biology studies by Real-Time PCR, 

Western blot, Southern blot, cell transfection, cyto- and 

histo-chemistry, in situ hybridization. 

Molecular diagnosis and functional studies of monogenic 

diabetes. Positron emission tomography in human 

(PET) and experimental animals (microPET). 


Alterations of cerebral glucose metabolism in pathophysiological 

states of feeding behaviour. 

Experimental evidence that GLP-1 modulates the cerebral 

expression of AMPK and of other metabolic sensors. 

The synergistic effects of GLP-2 and EGF, PDGF, IGF-I 

and insulin on the proliferation of rat astrocytes. 

The transduction of signals induced by GLP-1 in hMSC 

and its effects on proliferative and cytoprotective actions. 

Role of this peptide as an inhibitor of adipogenesis. 

The identification of GLP-1 and its receptor in mouse 

embryonic stem cells and in the early stages of mouse 

embryonic development. 

The identification of and functional interactions between 

GK and GKRP during development. 

Molecular diagnosis and functional characterization of 

new mutations of GK and HNF-1alpha genes. 

Glucokinase (GK) and glucokinase regulatory protein (GKRP) 

detection in the hypothalamus and the cerebral cortex (A, B). 

Immunofluorescent detection of GK (green, b) or GKRP (red, c) proteins 

in ventromedial hypothalamic nucleus (A) or parietal cortex (B) 

in the same brain slides from F-21. The arrows (d) indicate the double 

positive cells for GK and GKRP. Nuclear staining (a) was carried out 

in blue with 4,6-diamido-2-phenylindole (DAPI). (C) Western-blot detection 

of GKRP in GK immunoprecipitates, obtained after incubation 

of tissues homogenates from the F-21 hypothalamus (HT) and the 

adult rat liver with GK antibody. IP, immunoprecipitation. 


To continue the study of brain glucose metabolism in 

patients with bulimia, anorexia nervosa and compulsive 

obesity and the effects of specific treatments in these 

patients. 

To investigate cerebral carbohydrate metabolism in diabetic 

patients with or without obesity (an approach to 

central insulin resistance); the actions of anorexigenic 

and orexigenic peptides on metabolic sensors; the molecular 

mechanisms implied in the effects of GLP-2 on 

rat astrocytes; and the role of GLP-1 on embryonic development 

and cell differentiation. 

To analyse target genes for GLP-1 during stem cell 

differentiation. 

A) ES cells obtained from inner cell mass of blastocyst expressed 

GLP-1R in both Oct-4 positive and negative cells. Also, the GLP-1 

peptide is present in some ES cells, together with the GLP-1R. B) 

GLP-1 and GLP-R were present in the initial stages of mouse development 

(E6.0 and E8.0). C) mRNA of GLP-1R was detected in 

several tissues from E12.5 mice embryos. 


111

Publications 


Roncero I, Sanz C, Alvarez E, Vázquez P, Barrio PA, 

Blázquez E. Glucokinase and glucokinase regulatory 

proteins are functionally coexpressed before birth in the 

rat brain. J Neuroendocrinol, 21, 973-981 (2009) 

Velázquez E, Blázquez E, Ruiz-Albusac JM. Synergistic 

effect of glucagon-like peptide 2 (GLP-2) and of key 

growth factors on the proliferation of cultured rat astrocytes. 

Evidence for reciprocal upregulation of the 

mRNAs for GLP-2 and IGF-I receptors. Mol Neurobiol, 

40, 183-193 (2009) 




on the regulation of energy homeostasis in the 

central nervous system. From animal models to humans 



Álvarez, Enrique Blázquez, Deborah Burks, Mario Vallejo 



monogenic diabetes: from the bench to the bedside 

MODIAB: 2009-2010 

Principal Investigators: Luis Castaño, Enrique Blázquez, 

Jorge Ferrer, Mario Vallejo 


Ministerio de Ciencia y Tecnología, SAF2006-04075: 


Principal Investigator: Enrique Blázquez 


Estudio funcional de mutaciones en los factores de 

transcripción HNF-1A y HNF-1B asociados a diabetes 

monogénica 

UCM-Comunidad Autónoma de Madrid, CCG08-UCM/ 

SAL-3623: 2009 

Principal Investigator: María Ángeles Navas 

Programa de Creación y Consolidación de Grupos de 

Investigación Universidad Complutense-Comunidad 

Autónoma de Madrid al Grupo «Sensores cerebrales de 

glucosa, control de la saciedad, obesidad y diabetes tipo 2» 

UCM-Comunidad Autónoma de Madrid, 920808: 



Private funds 

Caracterización del mecanismo neuroprotector de 

GLP-1 y GLP-2 en cerebro. Potencial aplicación de estos 

péptidos en enfermedades neurodegenerativas 

Fundación Médica Mutua Madrileña: 2008-2011 

Principal Investigator: Elvira Álvarez ■ 


Efectos de los péptidos semejantes al glucagon GLP- 

1 y GLP-2 y otros péptidos anorexigénicos y orexigénicos 

sobre el metabolismo de la glucosa y el contenido 

de serotonina y su relector 1A en cerebro de rata 

MICINN, SAF2009-11-297: 2009-2012 


Estudio de los mecanismos moleculares de la Diabetes 

monogénica. Identificación y caracterización funcional 

de mutaciones MODY. Aislamiento de nuevos elementos 

implicados en la regulación de la glucoquinasa 


Sanitaria, PI060153: 2006-2009 

Principal Investigator: María Ángeles Navas 

Efectos de los péptidos semejantes al glucagón GLP- 

1 y GLP-2 sobre la expresión génica y actividades de 

glucoquinasa, AMP y PAS quinasas en cerebro 

Synergistic effects of GLP-2 and EGF, PDGF, IGF-I or Insulin on [3H] 

thymidine incorporation into DNA (A), cell density (B), intracellular 

cAMP production (C), and phospho-ERK1/2 expression (D) of rat astrocytes 

incubated for 20h, 26h, 30min and 5 min, respectively. Effect 

of IGF-I on GLP-2R mRNA expression (E) and effect of GLP-2 on 

IGF-IR mRNA expression (F) after 4h incubation. 

112 CibeRdem

Transgenic animal models and gene therapy 

approaches for diabetes 

Centre de Biotecnologia Animal i Teràpia Gènica, Universitat Autònoma de Barcelona 

http://cbateg.uab.cat 

Principal Investigator Fàtima Bosch Associate researcher Ana Carretero, Tura Ferré, Sylvie Franckhauser, Miquel García, Xavier 

Leon, Maria Molas, Sergio Antonio Muñoz, Víctor Nacher, Marc Navarro, Pedro José Otaegui, Anna Pujol, Martí Pumarola, Efren Riu, 

Jesús Ruberte, Anna Serafin Postdoctoral fellow Judith Agudo, Eduard Ayuso, Alba Casellas, Christopher Mann, Mercè Obach, 

Sabrina Tafuro PhD student Xavier Anguela, David Callejas, Ivet Elias, Verónica Jiménez, Albert Ribera, Carles Roca, Albert Ruzo, 

Pilar Villacampa Lab technician Jennifer Barrero, Marta Moya, Mireia Zaguirre Administrative staff Montse Bellido 

Keywords 

Beta-cell signal transduction. Gene therapy. Insulin sensitivity 

and resistance. Neuropathy-somatic. Retinopathy. 


We are studying the physiopathological causes of diabetes 

mellitus and its secondary complications as well as 

developing gene-therapy approaches to treat this disease. 

To achieve this, we are analysing transgenic models 

in which we have altered key genes in metabolic regulation. 

Additionally, based upon the studies in these models, 

we are developing a number of promising gene-therapy 

applications to treat diabetes using either viral or non-viral 

approaches to transfer the genes of interest in vivo. 


The study of the causes and pathophysiological 

mechanisms of diabetes mellitus using transgenic 

animal models. Analysis of the role of metabolic pathways 

in the development of insulin resistance and 

obesity, and the investigation of the molecular mechanisms 

involved in secondary complications (retinopathy, 

neuropathy). 

The development of new gene-therapy approaches 

for the treatment of diabetes mellitus based on the 

manipulation of skeletal muscle and the liver to increase 

glucose uptake, and induce pancreas regeneration 

in vivo. 


The generation of transgenic and knock-out animal 

models. 

The generation of viral vectors (adenovirus and adenoassociated 

virus). 

Gene transfer to cells in culture and to liver, skeletal 


113

muscle, adipose tissue, brain and pancreatic beta cells 

in vivo using viral and non-viral vectors. 

Metabolic phenotyping (in vitro and in vivo). 

Gene and protein expression analysis. 

Morphological, immunohistochemical and histopathological 

characterization. In vivo imaging. 


We showed that in genetically engineered mice: phosphofructo-1-kinase 

deficiency leads to a severe cardiac 

and haematological disorder in addition to skeletal muscle 

glycogenosis; increased intraocular IGF-I triggers 

blood-retinal barrier breakdown; and high AAV vector 

purity results in serotype- and tissue-independent enhancement 

of transduction efficiency. 

We also characterized a new perivascular macrophage 

with scavenger function, different from microglia, in 

physiological conditions and during retinopathy. 


To identify in adipose tissue and the liver new genes 

which predispose to type 2 diabetes using transcriptomic 

analysis and genetically engineered mice. 

To regenerate pancreatic beta-cell mass by in vivo expression 

of key growth factors that induce beta-cell 

replication and prevent beta-cell death. 

To develop gene therapy approaches for retinopathy 

using antiangiogenic factors. 

To undertake a preclinical trial in diabetic companion 

dogs of a combined insulin and GK gene therapy to 

increase skeletal muscle glucose uptake. 

Publications 


Haurigot V, Villacampa P, Ribera A, Llombart C, Bosch 

A, Nacher V, Ramos D, Ayuso E, Segovia JC, Bueren 

JA, Ruberte J, Bosch F. Increased intraocular insulinlike 

growth factor-I triggers blood-retinal barrier breakdown. 

J Biol Chem, 284, 22961-22969 (2009) 

Lebrun P, Cognard E, Bellon-Paul R, Gontard P, Filloux 

C, Jehl-Pietri C, Grimaldi P, Samson M, Pénicaud L, 

Ruberte J, Ferre T, Pujol A, Bosch F, Van Obberghen 

E. Constitutive expression of suppressor of cytokine signalling-3 

in skeletal muscle leads to reduced mobility and 

overweight in mice. Diabetologia, 52, 2201-2212 (2009) 

Mendes-Jorge L, Ramos D, Luppo M, Llombart C, 

Alexandre-Pires G, Nacher V, Melgarejo V, Correia M, 

Navarro M, Carretero A, Tafuro S, Rodriguez-Baeza 

A, Esperança-Pina JA, Bosch F, Ruberte J. Scavenger 

function of resident autofluorescent perivascular macrophages 

and their contribution to the maintenance of 

the blood-retinal barrier. Invest Ophthalmol Vis Sci, 50, 

5997-6005 (2009) 

Tafuro S, Ayuso E, Zacchigna S, Zentilin L, Moimas S, 

Dore F, Giacca M. Inducible adeno-associated virus 

vectors promote functional angiogenesis in adult organisms 

via regulated vascular endothelial growth factor 

expression. Cardiovasc Res, 83, 663-671 (2009) 

Editorial 

Bosch F. Gene and cellular therapy in Spain: moving 

forward. Hum Gene Ther, 20, 919 (2009) 



Identification of the genes regulated by the SIRT1 histone 

deacetylase and their contribution in the pathogenesis 

of type 2 diabetes and obesity 

EU, Marie Curie International Reintegration Grant, 

MIRG-CT-2007-207745: 2009-2011 

Principal Investigator: Efren Riu 

INFRAFRONTIER. The European Infrastructure for phenotyping, 

archiving and dissemination of disease models 

EU, European Strategy Forum on Research Infrastructures, 

FP7-INFRA-STRUCTURES-2007-1: 2008-2011 

Principal Investigator: Fàtima Bosch 

Project coordinator: Martin Hrabé d’Angelis, GSF 

National Research Centre for Environment and Health/ 

HGF, Germany 

EUMODIC. The European Mouse Disease Clinic. A 

distributed phenotyping resource for studying human 

disease 

EU, Integrated Project FP6-2005-LIFESCIHEALTH-6, 

LSHG-CT-2006-037188: 2007-2011 


Project coordinator: Steve Brown, Medical Research 

Council, UK 

CLINIGENE. European Network for the Advancement 

of Clinical Gene Transfer and Therapy 

EU, Network of Excellence, FP6-2004-LIFESCIHEALTH-5, 

LSHB-CT-2006-018933: 2006-2011 


114 CibeRdem

Project coordinator: Odile Cohen-Haguenauer, École 

Normale Supérieure de Cachan, France 

EUGENE2. European Network on Functional Genomics 

of Type 2 Diabetes 

EU, Network of Excellence, LIFESCIHEALTH, LSHM- 

CT-2004-512013: 2004-2009 


Project coordinator: Ulf Smith, Göteborgs Universitet, 

Sweden 


Estudio del papel de los factores de crecimiento similares 

a la insulina en la regeneración de la célula beta 

pancreática 

Ministerio de Educación y Ciencia, Plan Nacional I+D+i, 

SAF2008-00962: 2009-2011 


Estudio del efecto de la deacetilación de cromatina por 

miembros de la familia de las sirtuinas en la patogénesis 

de la resistencia a la insulina y diabetes tipo 2 

Ministerio de Ciencia e Innovación, Plan Nacional 

I+D+i, SAF2008-03083: 2009-2011 

Principal Investigator: Efren Riu 

Atlas morfológico para el fenotipado de ratones mutantes 

Ministerio de Ciencia e Innovación, SAF2008-0581-E: 


Principal Investigator: Jesús Ruberte 

Desarrollo de vectores adeno-asociados (AAV) para la 

terapia neuroprotectora en enfermedades degenerativas 

de la retina 

Proyectos TRACER, Ministerio de Ciencia e Innovación, 

in collaboration with ProRetina Therapeutics SL, 

PET2008_0282_02: 2009-2010 


Project coordinator: Enrique J de la Rosa 

Estudio de los mecanismos responsables de la retinopatía 

diabética y desarrollo de nuevas aproximaciones 

de terapia génica 

Instituto de Salud Carlos III, PI061417: 2007-2009 


Análisis de la función de un nuevo subtipo de macrófagos 

perivasculares de la retina en la patogenia de la 

degeneración macular asociada a la edad 


Principal Investigator: Jesús Ruberte 


Ajut per a grups de recerca consolidats 




Patents 


Composiciones de terapia génica para prevenir y/o 

tratar enfermedades autoinmunes 


Inventors: Xavier Anguela, Sabrina Tafuro, Fàtima Bosch 

Universidad Autònoma de Barcelona (2009) 

Awards 

«Best Abstract», “A new non-viral gene therapy approach 

to prevent type 1 diabetes by overexpressing 

IGF-I in the liver”, 17th ESGCT Annual Congress (2009) 

Awardees: X Anguela, S Tafuro, C Mann, J Agudo, 

D Callejas, M Obach, C Roca, A Ruzo, F Bosch 

«Vice President of the European Association for the 

Study of Diabetes», EASD (2009-2012) 

Awardee: Fàtima Bosch ■ 

Neuropatía Diabética: estudio de la expresión génica 

en la degeneración y posterior regeneración nerviosa 

en un modelo murino transgénico RIP/IFNbeta 

Instituto de Salud Carlos III, PI 05/0892: 2008-2011 

Principal Investigator: Martí Pumarola 

Estudio del papel de los leucotrienos en el desarrollo 

de la resistencia a la insulina y aterosclerosis asociadas 

a la obesidad 

Instituto de Salud Carlos III, PI07/0313: 2008-2010 

Principal Investigator: Sylvie Franckhauser 

A perivascular macrophage (PM) is localized on the surface of a 

retinal venule. L: lumen; E: endothelial cell; SM: smooth muscle 

cell; A: astrocyte; arrow indicates a lysosome. 


115

Laboratory of Molecular Endocrinology 

Centro de Investigación Príncipe Felipe, Valencia 

www.cipf.es 

Principal Investigator Deborah Burks Postdoctoral fellow Ana Sánchez, Silvia Sanz, Carlos 

Acosta, Luke Noon PhD student Maria Jesús Belda, Juan Martin, Verónica Moreno Lab manager 

Lorena Menes 

Keywords 

Beta-cell signal transduction. Insulin sensitivity and resistance. 

Islet degeneration and damage. Retinopathy. 

Stem cells. 


Insulin action at a molecular level is mediated 

by a complex signalling network; insulin binds to 

cell surface receptors and stimulates their intrinsic 

tyrosine kinase activity. 

Activated receptors engage and phosphorylate 

various cellular proteins, principally members of 

the insulin receptor substrate (IRS) protein family. 

Phosphorylated IRS proteins then recruit other 

signalling molecules such as Grb2 and PI3- 

kinase to activate pathways which ultimately determine 

the cellular response to insulin or IGF-I. 

Our work is based on the hypothesis that defective 

IRS signalling contributes to the pathophysiology 

of diabetes and other metabolic-related 

disorders, including obesity, neurodegeneration, 

atherosclerosis and retinal disease. 


Regulation of the cell-cycle in pancreatic beta cells. 

Given that beta-cell proliferation may represent one of 

the fundamental ways to avoid diabetes, it is of primary 

importance to identify the signalling pathways which 

regulate the expansion of existing insulin-producing 

cells. The absence of IRS-2 induces several cell-cycle 

defects in pancreatic islets and thus, our working hypothesis 

is that postnatal replication of beta cells requires 

IRS-2 signalling and we are working to identify 

the precise mechanisms. 

The role of IRS-2 signals in the differentiation of human 

embryonic stem cells to endoderm lineages. The 

differentiation of human embryonic stem cells (hESC) 

to specific cell-types is an important potential tool for 

generating cell-based therapies for metabolic diseases. 

Our global objective is to define the role of IRS signalling 

proteins in pluripotency and in the differentiation of 

the pancreatic and hepatic lineages. 

IRS-2 signalling in the regulation of neuronal function. 

Although the brain was initially considered as an organ 

insensitive to insulin action, it has become clear in recent 

years that reduced insulin signalling in the CNS 

116 CibeRdem

contributes to pathogenic metabolic disorders such as 

diabetes, obesity and metabolic syndrome. Deletion of 

IRS-2 in mice produces various neuronal abnormalities 

including impaired neurogenesis. One of our objectives 

is to measure glucose uptake in neurons and astrocytes 

isolated from wild type and IRS-2-/- mice in order 

to establish the role of IRS-2 in neuron-glia crosstalk. 

The role of insulin/IGF-I signalling in diabetic retinopathy. 

Increasing evidence suggests that neuronal 

degeneration contributes to DR before microvascular 

abnormalities are detectable. IRS-2 deficiency in mice 

causes a 50% loss of photoreceptors at two-weeks of 

age due to apoptosis. We are assessing whether resistance 

to insulin/IGF-I in the retina disables the molecular 

mechanisms which protect retinal cells against 

stress and apoptosis, thereby triggering neurodegeneration 

and DR. 


Insulin signal transduction. We use a variety of techniques 

to analyse insulin/IGF-I signalling including Western blotting, 

immunohistochemistry and kinase assays. 

The development and characterization of transgenic 

mouse models for the study of metabolic diseases. 

Glucose tolerance tests, glucose-stimulated insulin secretion, 

quantification of the beta-cell population, monitoring 

of food intake and adipose content, and behavioural testing 

aimed at assessing cognitive and motor function. 

The culture and differentiation of human embryonic 

stem cells. Our expertise extends to the genetic modification 

of these cultures via viral infection for silencing 

and overexpressing proteins of interest. 


Our major achievements this year include the development 

of feeder-free conditions for the efficient differentiation 

of hESC to definitive endoderm. Additionally, 

we have produced hESC reporter cell lines to monitor 

the expression of beta-cell markers (e.g. insulin, PdX1, 

IRS-1 and IRS-2) and hepatocyte markers. These tools 

have provided proof-of-concept that IRS proteins regulate 

insulin signalling in hESc. Using mouse models, we 

have established that beta-cell specific expression of 

placental lactogen hormone can rescue diabetes in IRS- 

2-deficient mice, demonstrating that the proliferative effects 

of this hormone do not require IRS-2 signals. 


We plan to use the cell-based tools and mouse models 

available in our laboratory to improve our understanding 

of the role of IRS proteins in metabolic diseases. 

We are particularly interested in employing the hESC 

technology we have developed in collaboration with 

CIBERDEM clinicians in order to generate in vitro models 

of relevant metabolic diseases; this will provide 

invaluable tools for correlating specific mutations with 

cellular defects. 






humans 

IRS-2-driven GFP expression in human embryonic stem cells. 


117










Ramon Gomis 










Development of Culture Conditions for the Differentiation 

of Human Embryonic Stem Cells to Hepatocytes 

European Union, Seventh Framework Programme, 

Health-20071.4-7: 2008-2011 

Principal Investigator: Deborah Burks 


El papel de IRS-2 en la regeneracion del pancreas 

endocrino 

Instituto de Salud Carlos III, Incorporación de Grupos 

Emergentes en SNS, EMER07/012: 2008-2012 

Principal Investigator: Deborah Burks 

Análisis de la Vía de Señalización Insulina/IRS-2 

Como un Link Molecular Entre Metabolismo Diabético 

y Neurodegeneración 

Ministerio de Educación y Ciencia, SAF2008-00011: 

2008-2011 

Principal Investigator: Deborah Burks ■ 

118 CibeRdem

Hospital de Cruces Diabetes Research Group 

Hospital de Cruces, Barakaldo 

www.hospitalcruces.com 

Principal Investigator Luis Castaño Associate researcher María Ángeles Aniel-Quiroga, 

Jose Ramon Bilbao, María Ángeles Busturia, Alicia Cortázar, Sonia Gaztambide, Pedro Martul, 

Guiomar Pérez de Nanclares, Itxaso Rica, Clara Isabel Rodríguez, Federico Vázquez, Amaia Vela 

Postdoctoral fellow Rosa María Martínez Research assistant Inés Urrutia PhD student Anibal 

Aguayo, Oihana Belar, Ainara Castellanos, Javier de las Heras, Eduardo Fernández, Intza Garín, 

Teba González, Izortze Santín Lab manager Galder Gutiérrez, Gustavo Pérez de Nanclares Nurse 

Alicia Cobo Nutritionist Ana María Megido Administrative staff Sorkunde Rivero 

Keywords 

Clinical diabetes. Genetics type 1 diabetes. Immunology 

(clinical). Oral pharmacological agents. Prediction/prevention 

of type 1 diabetes. 


Our group is a pioneer in the immunogenetics of type 1 

diabetes and other associated autoimmune conditions. 

The major advances are related to efforts to identify 

better disease predictors within international consortiums 

such as T1DGC (genetic markers) and DASP 

(autoantibody standardization), and we are directly 

involved in the European Type 1 Diabetes Genetics 

Network. We are also prominent in the characterization 

of novel genes responsible for monogenic diabetes, 

as well as in new therapeutic approaches for those 

patients with known genetic alteration, and form part 

of the European network for developing good clinical 

practice for monogenic diabetes. 

Our clinical research work is focused on type 1 diabetes 

prediction and prevention, together with the analysis 

of diabetes control and complications, and the 

development of new strategies to treat diabetes (CSI). 

Finally, research into obesity in children and adults is 

focused on the analysis of markers, the search for different 

behaviour in patients with and without diabetes 

and on new strategies for bariatric surgery. At a national 

level, we are part of the CIBERDEM Biobank, providing 

the scientific community with high-quality biological 

samples. 


The identification of additional genetic susceptibility 

markers for type 1 diabetes (common to other autoimmune 

conditions or exclusive to type 1 diabetes) 

and related autoimmune disorders in the extended 

MHC (6p21) and other regions using high throughput 

genotyping. 

The study of immune mediators of disease development, 

characterization of novel autoantigens/antibodies 

and cell populations in patients: Th1, Th2 and Th17 

responses. 

The identification of new genes responsible for monogenic 

diabetes by genome wide analysis (both CGI and 


119

CGH approaches). 

The molecular and clinical characterization of monogenic 

diabetes and new therapeutic strategies for K ATP 

channel alterations. 

The prediction and prevention of type 1 diabetes. 

The control of diabetes complications. 


Diabetes genetics and genomics: high throughput 

genotyping and gene expression analyses; pathway 

analysis and functional polymorphism selection; gene 

disease association studies in complex diseases. 

The immunohistochemistry of immune markers/ 

autoantigens. 

The molecular characterization of monogenic diabetes. 

Gestational diabetes. 

New methods for diabetes control and treatment. 

Immune prevention of type 1 diabetes. 


The localization of a functional variant in the MHC that 

modulates risk to type 1 diabetes conferred by DR3 

haplotypes. 

The identification of mutations in the INS promoter associated 

with neonatal diabetes. 

The characterization of allelic loss at GCK and HNF1a 

associated with monogenic diabetes. 

Type 1 diabetes nutritional or antigen prevention in 

2009. 

Genoma España Biobank 2009 targets. 

Diabcare data on control and complications from 2006 

to 2009. 

The quality of life in children with diabetes under 11 

years. 

A national guide for type 1 diabetes care. 


The validation of pathogenicity of variants at INS, 

KCNJ11 and ABCC8 and characterization of new 

genes. 

The analysis of haplotype segregation in MODY families 

for gene discovery. 

The analysis of Diabcare data on diabetes control and 


New prevention strategies for type 1 diabetes. 

A national guide for type 1 diabetes care. 

National epidemiology for diabetes. 

The confirmation of novel risk loci in other population/ 

autoimmune disorders. 

Functional studies of the effect of implicated 

polymorphisms. 

The resequencing of implicated chromosomal regions 

in search of rare risk variants. 

Publications 


Garin I, Martinez R, de las Heras J, Perez-Nanclares G, 

Castano L, Perez de Nanclares G; Spanish GEDIMO 

Group. Mutations in MAFA and IAPP are not a common 

cause of monogenic diabetes. Diabet Med, 26, 746- 


Martín-Frías M, Colino E, Pérez de Nanclares G, 

Alonso M, Ros P, Barrio R. Glibenclamide treatment in 

relapsed transient neonatal diabetes as a result of a 

KCNJ11 activating mutation (N48D). Diabet Med, 26, 

567-569 (2009) 

Ricart W, López J, Mozas J, Pericot A, Sancho MA, 

González N, Balsells M, Luna R, Cortázar A, Navarro 

P, Ramírez O, Flández B, Pallardo LF, Hernández A, 

Ampudia J, Fernández-Real JM, Hernández-Aguado I, 

Corcoy R; Spanish Group for the study of the impact 

of Carpenter and Coustan GDM thresholds. Maternal 

glucose tolerance status influences the risk of macrosomia 

in male but not in female fetuses. J Epidemiol 

Community Health, 63, 64-68 (2009) 

Santin I, Castellanos-Rubio A, Aransay AM, Gutierrez 

G, Gaztambide S, Rica I, Vicario JL, Noble JA, Castaño 

L, Bilbao JR. Exploring the diabetogenicity of the HLA- 

B18-DR3 CEH: independent association with T1D genetic 

risk close to HLA-DOA. Genes Immun, 10, 596- 


Review 

Castaño L, Pérez de Nanclares G, Vela A. Hipoglucemia 

por Hiperinsulinismo Neonatal. Revista Española de 

Pediatría, 65, 495-508 (2009) 

Rica I, Pérez de Nanclares G, Castaño L. Diabetes 

neonatal: defectos genéticos en la función de la célula 

beta pancreática. Enfoque diagnóstico y tratamiento. 

Revista Española de Pediatría, 65, 478-487 (2009) 

Ruiz de Adana M, Rigla M, Vidal P. Consenso sobre el uso 

de la monitorización continua de glucosa. Documento 

de Posicionamiento. Av Diabetol, 25, 96-98 (2009) 

120 CibeRdem

Vela A, García Z, Goñi A, Suinaga I, Aguayo A, de las 

Heras J, Grau G, Rica I, Martul P. Plan de intervención 

en la prevención de obesidad infantil «Erosotasuna 

Zainduz». Revista Española de Obesidad, 7, 91-96 


Book chapter 

Castaño L, Perez de Nanclares G, Bilbao JR. «Bases 

Genéticas de la diabetes tipo 1», in Tratado de endocrinología 

pediátrica, 4th Edition. McGraw-Hill, 740-747 


Figuerola D, Reynals E, Ruiz M Vidal A, Castaño L. 

«Diabetes mellitus», in Tratado de Medicina Interna 

Farreras Rozman, 16th Edition. Elsevier, 1955-1988 


Vázquez San Miguel F, Goñi Iriarte MJ, Martínez N. 

«Retinografía con cámara de retina no midriática para 

el cribado de la retinopatía diabética», in Tecnologías 

aplicadas a la diabetes. Sociedad Española de 

Diabetes, 103-124 (2009) 









International project 

Trial to reduce IDDM in children at genetic risk. TRIGR 

National Institutes of Health, 5U01HD040364-08: 

2007-2011 

Principal Investigator: Luis Castaño 

Project coordinator: Hans Akerbloom 


Encapsulación de islotes pancreáticos de ratón: 

Análisis de la funcionalidad y revascularización in vitro 

e in vivo 

Departamento de Industria Gobierno Vasco, SAIO09- 

PE09: 2009-2010 


Etiopatogenia de los trastornos autoinmunes: Diabetes 

mellitus tipo 1 y Enfermedad celíaca 

Departamento de Educación Gobierno Vasco, IT-472- 

07: 2007-2012 


Investigación de nuevas dianas terapéuticas en autoinmunidad: 

Bloqueo de la ruta NFKkappabeta en enfermedad 

celíaca 

Departamento de Industria Gobierno Vasco, SAIO08- 

PE08BF03: 2008-2010 

Principal Investigator: Jose Ramon Bilbao 

Polimorfismos estructurales y de variación en el número 

de copias de genes de la respuesta inmune innata 

en enfermedad celíaca 

Departamento de Sanidad Gobierno Vasco, 

2006111030: 2007-2009 


Private funds 

Creación del Banco Nacional de ADN. Nodo de 

Enfermedades Metabólicas 




Perfil de expresión de los receptores KIR en 

la enfermedad celiaca: estudios cualitativos y 

cuantitativos 

Instituto de Salud Carlos III, PI070796: 2008-2010 


Búsqueda de nuevos genes responsables en la diabetes 

monogénica 


Principal Investigator: Guiomar Pérez de Nanclares 

Mouse pancreatic islets encapsulated. 


121


Estudio aleatorizado, controlado frente a placebo, doble 

ciego, paralelo y multicéntrico para evaluar antagonistas 

de IL-1 en sujetos con diabetes tipo 1 de reciente 

diagnóstico. AIDA. EudraCT 2007-007146-34. Phase II 

Steno Diabetes Center: 2009-2010 

Researchers: Sonia Gaztambide, Federico Vázquez, 

María Dolores Moure, Ana Moreno, Paz Gallego 

Estudio multicéntrico, randomizado, abierto, doble 

ciego, con doble enmascaramiento, controlado frente a 

un comparador activo para evaluar eficacia, seguridad 

y tolerancia de taspoglutida (RO5073031) comparado 

con pioglitazona en pacientes con diabetes mellitas 

tipo 2 controlados inadecuadamente con sulfonilurea 

(SU) en monoterapia o con la combinación metformina 

mas sulfonilurea. Phase II 

Hoffmann-La Roche: 2009-2010 

Researchers: Javier Santamaría, Alicia Cortázar 

A multicenter, randomized, double-blind, placebo-controlled 

study to evaluate cardiovascular outcomes following 

treatment with alogliptin in addition to standard 

of care in subjects with type 2 diabetes and acute coronary 

syndrome. EudraCT 2009-011222-34. Phase III 

Takeda: 2009-2010 

Researchers: Sonia Gaztambide, Amaya Uriarte, Juan 

García, Ana Moreno, Rosa Axpe 

A phase III 3 arm randomized double-blind placebo 

controlled multicenter study to investigate the impact of 

Diamyd on the progression of diabetes in patients newly 

diagnosed with type 1 diabetes mellitus. D/P3/07/4 

Dyamid Therapeutics: 2008-2010 

Researchers: Luis Castaño, Itxaso Rica 

European prescription survey of short acting insulin analogues 

in children and adolescents. DIREG_R_04154. 

EPIC Study. Phase IV 


Steering Committee Member: Luis Castaño 

pacientes con obesidad abdominal y microalbuminuria, 

con diabetes mellitus tipo 2 o dislipemia, con o sin otros 

factores de riesgo cardiometabólico. RIMON_L_01031. 

Phase III 


Researchers: Sonia Gaztambide, Amaya Uriarte, Ana 

Moreno, Paz Gallego 

Estudio multicéntrico, internacional, aleatorizado y de 

diseño factorial 2x2, para evaluar los efectos de lantus® 

(insulina glargina) frente al tratamiento estándar, 

y de los ácidos grasos omega-3 frente al placebo, en 

la reducción de la morbilidad y la mortalidad cardiovascular 

en sujetos de alto riesgo con alteración de la 

glucosa en ayunas (aga), disminución de la tolerancia 

a la glucosa (dtg) o diabetes mellitus de tipo 2 en 

fase inicial: ensayo ORIGIN 2008 Annual Report 111 

(outcome reduction with initial glargine intervention). 

HOE9901/4032ORIGIN. Phase III 


Researchers: Sonia Gaztambide, Ignacio Goicolea, 

Yolanda Salgado 

Estudio multinacional, aleatorizado, doble ciego, controlado 

con placebo, titulación forzada y diseño factorial 

2x2, sobre la eficacia y seguridad de la administración 

a largo plazo de nateglinida y valsartán, en la prevención 

de la diabetes y de acontecimientos cardiovasculares 

en sujetos con tolerancia alterada a la glucosa. 

CDJN608B2302 (NAVIGATOR). Phase III 

Novartis: 2002-2009 

Researchers: Sonia Gaztambide, Federico Vázquez, 

Ana Moreno, Pilar Alonso 


Continous Glucose Monitoring Consensus (2009) 

Sociedad Española de Diabetes (SED) 

Authors: Vázquez F, Ruiz de Adana M ■ 

European Postmarketing observational prospective cohort 

study of children with type 1 diabetes treated with 

apidra. APIDR_C_03909. OCAPI Study. Phase IV 


Steering Committee Member: Luis Castaño 

Estudio multicéntrico,aleatorizado, doble ciego, de dos 

grupos paralelos, controlado con placebo y de 12 meses 

de duración de los efectos de rimonabant 20 mg en 

122 CibeRdem

Proinsulin and tyrosine hydroxilase in 

development and differentiation 

Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid 

www.cib.csic.es 

Principal Investigator Flora de Pablo Associate researcher Catalina Hernández Postdoctoral 

fellow Patricia Vázquez Lab technician Cayetana Murillo 

Keywords 

Catecholamines. Hormone receptors. Islet development. 

Proinsulin. Transcription factors. 


It has been shown that tyrosine hydroxilase (TH) is expressed 

in the pancreatic primordium from E 9.5, but it is 

not known whether TH (or any catecholamine in the biosynthetic 

pathway initiated by this enzyme) is required for 

the correct differentiation of islet cells. Neither has it been 

characterized what role proinsulin and TH play in cardiac 

development. 

Unprocessed proinsulin is expressed prior to pancreas 

development, and chimeric transcripts originated by the 

fusion of the TH mRNA and that of insulin, are also expressed 

in early embryogenesis. 


The characterization of TH expression in mouse pancreas 

development. 

The analysis of TH function by studying pancreatic cell 

markers in TH-/- developing mice. 

The analysis of TH haploinsufficient adult mice relative to 

blood pressure and insulin sensitivity. 

The roles of proinsulin and TH in cardiac organogenesis 

and cardiomyocyte differentiation. 

The modulation of cell survival/death by proinsulin. 

The regulation of stem cell differentiation. 


Development mechanisms of chick and mouse embryos. 

The culture of whole embryos and pancreas explants. 

Proinsulin signalling in developing embryos, explants and 

cell lines. 

Immunocytochemistry, in situ hybridization and qRT-PCR 

of the pancreas. 

Genetic and pharmacological loss/gain of function approaches 

in whole chick embryo and pancreas explants. 


The demonstration of mTH mRNA expression in mouse 

embryos from E6.5 onwards and in the pancreas from 


123

E11.5 to E18.5. At these stages dopamine receptors D1- 

D5 are expressed in the pancreas. L-DOPA and dopamine 

are detected in increasing levels in E7,5, E8,5 and 

E9,5 whole embryos. 

About 90% of E13.5 TH+ cells in WT pancreas are glucagon+. 

In the TH-/- mice pancreas, there is an increase in 

the number of glucagon+ cells. 

TH is required in chick embryos for the correct development 

of cardiac chambers. L-DOPA and dopamine increase 

the expression of transcription factors of cardiomyocyte 

lineage and of contractile proteins. 

Publications 


Roncero I, Sanz C, Alvarez E, Vázquez P, Barrio PA, 

Blázquez E. Glucokinase and glucokinase regulatory 

proteins are functionally coexpressed before birth in the 

rat brain. J Neuroendocrinol, 21, 973-981 (2009) 

Book 

de Pablo F, Cascales M (Eds). Células madre y terapia 

regenerativa. Real Academia Nacional de Farmacia 



To characterize further the subpopulation of TH+ cells 

in relation to glucagon, insulin and other pancreatic 

markers from E12.5 to E18.5. To confirm the phenotype 

in the pancreas of TH-/- mice, and try to rescue it 

by pharmacological and genetic approaches using organotypic 

cultures of the pancreas. 

To characterize the effect of L-DOPA and dopamine in 

stem cell differentiation towards a cardiac lineage. 

To analyse the effect of proinsulin on the differentiation 

of cardiomyocytes in vivo and in vitro. 



Transcritos quimera y otras formas atípicas de regulación 

génica y sus implicaciones en el desarrollo 

temprano 


2007-2010 

Principal Investigators: Catalina Hernández, Flora de Pablo 

Patents 


Use of catecholamine for the differentiation of stem 

cells to cardiomyocytes 

Patent application number: PCT/ES09/070339 

Inventors: Catalina Hernández, Flora de Pablo, Óscar 

Bártulos, Amelia Aránega 

CIB/CSIC and University of Jaén (2009) ■ 

Coexpression of glucagon and TH in pancreatic endocrine precursors 

at E12.5. Confocal Core Facility CIB. 

124 CibeRdem

Genomic programming of beta cells 

Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona 

www.betacellregulation.net 

Principal Investigator Jorge Ferrer Postdoctoral fellow Ildem Akerman, Miguel Ángel Maestro, 

Takao Nammo, Lorenzo Pasquali PhD student Ignasi Moran, Myriam Solar, Joris van Arensbergen 

Lab manager Carme Sanahuja Lab technician Xavier García, Vanesa Grau 

Keywords 

Genetics type 2 diabetes. Genomics. Islet development. 

Transcription factors. 


This lab is interested in understanding the transcriptional 

regulation of the development and function of 

differentiated pancreatic beta cells. 

We are particularly interested in the implications of this 

area for human diabetes. 


Our main lines of research are: mouse genetic analysis 

of beta-cell regulation; understanding the epigenome of 

pancreatic beta cells and its implications for the development, 

plasticity and growth of beta cells; and the regeneration 

of pancreatic beta cells. 


Beta-cell differentiation and regeneration. 

Mouse genetics. 

Monogenic diabetes. 

Epigenetics and chromatin biology. 

Large-scale chromatin and gene expression analysis. 


During 2009 we have reported two key studies for our 

understanding of the molecular defect underlying the 

most common cause of monogenic diabetes, which results 

from mutations in HNF1A (Servitja et al., Mol Cell 

Biol, 2009; Boj et al., Diabetes, 2009) and collaborated 

in a study to understand the function of another monogenic 

diabetes gene, PDX1 (Gauthier et al., Cell Metab, 

2009). Using a combination of mouse genetic models 

and genome-wide gene expression and ChIP analyses, 

we discovered the tissue-specific programmes controlled 

by the transcription factor HNF1A in islets and 

the liver. Another set of studies addressed the evolutionary 

conservation of HNF1A function, and showed 

that, despite the fact that HNF1A binds to many different 

sites in mouse and human genomes, its regulatory 

function is largely conserved. These results provide 


125

the basis for ongoing efforts to define new therapeutic 

strategies to treat this form of diabetes. 

During this year we also completed a lineage tracing 

analysis of pancreatic duct cells (Solar et al., 

Dev Cell, 2009, see also comment in Kushner et al., 

Cell Metab, 2010). It has long been assumed that 

embryonic and adult pancreatic duct cells act as 

progenitors of beta cells. This question is central for 

diabetes therapeutics because one of the most important 

goals in this field is to identify the cell types 

that need to be targeted to induce regeneration of 

beta cells. Our approach to address this stems from 

our earlier description that HNF1B, another monogenic 

diabetes gene, is selectively expressed in 

pancreatic duct cells. At that time there were no reliable 

duct-cell-specific markers, and, with support 

from the core facility from CIBERDEM investigator 

Dr Bosch, we exploited this information to generate 

a mouse model to trace pancreatic duct cells. 

Our results showed that embryonic ducts act as endocrine 

cell progenitors, but once they differentiate 

they do not give rise to any other pancreatic cell 

types, even during regeneration. 

In collaboration with CIBERDEM and CIBERER members 

in Bilbao, we have characterized a novel mechanism 

of diabetes which caused mutations in the insulin 

gene. Finally, we have implemented high throughput 

sequencing and microarray technologies to dissect the 

epigenetic mechanisms underlying beta-cell identity. 

These studies were also carried out in collaboration 

with CIBERDEM members in IDIBELL. 

Publications 


Boj SF, Servitja JM, Martin D, Rios M, Talianidis I, Guigo 

R, Ferrer J. Functional targets of the monogenic diabetes 

transcription factors HNF-1alpha and HNF-4alpha 

are highly conserved between mice and humans. 

Diabetes, 58, 1245-1253 (2009) 

Gauthier BR, Wiederkehr A, Baquié M, Dai C, Powers 

AC, Kerr-Conte J, Pattou F, MacDonald RJ, Ferrer J, 

Wollheim CB. PDX1 deficiency causes mitochondrial 

dysfunction and defective insulin secretion through 

TFAM suppression. Cell Metab, 10, 110-118 (2009) 

Chromatin landscape of the PDX1 locus: top panel depicts the location of FAIRE sites in islets (blue) or in any of five ENCODE 

(red), and CTCF binding in K562 cells; bottom panel shows a portion of the CORE (cluster of open chromatin), with islet-selective 

open chromatin sites at previously characterized regulatory elements (Area I-III, Area IV) and in an evolutionarily conserved putative 

enhancer. Image from: Gaulton KJ, Nammo T, Pasquali L, Simon JM, Giresi P, Fogarty MP, Panhuis TM, Mieczkowski P, Secchi A, 

Bosco D, Montanya E, Berny T, Mohlke KL, Lieb JD, Ferrer J. A map of open chromatin in human pancreatic islets. Nat Genet (2010). 

126 CibeRdem

Servitja JM, Pignatelli M, Maestro MA, Cardalda C, 

Boj SF, Lozano J, Blanco E, Lafuente A, McCarthy MI, 

Sumoy L, Guigó R, Ferrer J. Hnf1alpha (MODY3) controls 

tissue-specific transcriptional programs and exerts 

opposed effects on cell growth in pancreatic islets and 

liver. Mol Cell Biol, 29, 2945-2959 (2009) 

Solar M, Cardalda C, Houbracken I, Martín M, Maestro 

MA, De Medts N, Xu X, Grau V, Heimberg H, Bouwens 

L, Ferrer J. Pancreatic exocrine duct cells give rise to 

insulin-producing beta cells during embryogenesis but 

not after birth. Dev Cell, 17, 849-860 (2009) 


Regulación Epigenética y Plasticidad de las Células 

Beta Pancreáticas 



Principal Investigator: Jorge Ferrer 

Private funds 

Analysis of the plasticity of pancreatic duct cells 

Juvenile Diabetes Research Foundation, 26-2008-633: 

2008-2010 

Principal Investigator: Jorge Ferrer ■ 

Book chapter 

Ferrer J, Maestro MA, Fernández-Blasells M. «Bases 

genéticas de las enfermedades endocrinas», in Tratado 

de endocrinología pediátrica, 4th Edition. McGraw-Hill 











Biology of Liver and Pancreatic Development and 

Disease 

European Union, 238821: 2009-2013 


Collaborative European Effort to Develop Diabetes 

Diagnosis 

European Union, 223211: 2008-2012 


EURODIA. Functional genomics of pancreatic beta 

cells and of tissues involved in control of the endocrine 

pancreas for prevention and treatment of type 2 

diabetes 

European Union, LSHM-CT-2006-518153: 2006-2010 


Betacelltherapy. Beta Cell Programming for Treatment 

of Diabetes 

European Union, LSHB-CT-200-512145: 2005-2010 



127

Diabetes and obesity: biopathology 

and cellular plasticity 


www.diabetisiobesitat.org 

Principal Investigator Ramon Gomis Associate researcher Roser Casamitjana, Ignacio Conget, 

Enric Esmatjes, Lilliam Flores, Rosa Gasa, Felicia Hanzu, Marga Jiménez, Belén Nadal, Marcelina 

Parrizas, Josep Vidal Postdoctoral fellow Marc Claret, María José Coves, Rebeca Fernández, 

Nathalie Nicod, Sandra Rebuffat PhD student Jordi Altirriba, Marta Amigó, Joana Duarte, Míriam 

Ejarque, Katerina Papageorgiou, Fabián Pardo, Gemma Pujadas Lab manager Marta Julià 

Lab technician Yaiza Esteban, Ainhoa García, Sandra Piquer, Lídia Sánchez 

Keywords 

Clinical diabetes. Endothelium. Islet degeneration and 

damage. Islet development. Weight regulation and obesity. 


Our team focuses its research on the characterization 

of the molecular basis of crosstalk between peripheral 

tissues and beta cells in order to improve the knowledge 

and understanding of the aetiopathogenesis of 

diabetes mellitus and obesity. One of the main pillars 

of our activity is the fight against the main causes of 

morbidity associated with diabetic patients, with special 

emphasis on endothelial disease. The research projects 

which are currently being carried out by our team 

will lead to results that can be applied in the short term 

to the improvement of the diagnosis and treatment of 

diabetes mellitus and obesity, as well as their degenerative 



The effects of pancreatic-mesenteric adipose tissue on 

cellular plasticity, especially in the islet of Langerhans. 

Crosstalk between adipose tissue and endothelium in 

obesity and type 2 diabetes and therefore the role of 

adipocytokines in the aetiology and development of the 

atherothrombotic complications in these two diseases. 

The molecular determinants involved in pancreatic betacell 

apoptosis and regeneration - clinical applications. 

Transcriptional networks which control beta-cell population 

and function. 

Metabolic and molecular targets of the antidiabetic effect 

of sodium tungstate. 

The role of the hypothalamus in energy homeostasis 

control in obesity. 

The epigenetic regulation of adipogenesis. 

The molecular effects of the TCF7L2 single nucleotide 

polymorphism (SNP) rs7903146 and its role in the risk 

of type 2 diabetes. 


Human and rodent pancreatic islet isolation and culture. 

Human adipocyte isolation and culture. 

Morphometric analysis of the pancreas. 

128 CibeRdem

Euglycaemic clamps in humans and in experimental 

animal models. 

Calorimetric studies in human and in experimental 

models. 

Genomic, proteomic and systems biology analysis. 

Adenoviral and lentiviral infection of cells. 

Clinical studies (phase 1 and phase 2, in pharmacological 

trials). 

In vivo and in vitro methods to measure endothelial 

dysfunction. 

Epigenetic methods for analysis. 

Hormone/nutrient sensitivity tests, feeding behaviour, 

metabolic rate, hypothalamic function analysis. 

Huvec model (endothelial physiology analysis). 

Cell therapy trials. 


A description of the molecular pathway involved in the 

antidiabetic and antiobesity effects of tungstate administration 

in experimental animal models. 

Targets of tungstate treatment in diabetes and obesity 

- the impact on PTP-1B. 

A description of the modulating effects of the function 

of neuroD1 and neurogenin3 transcription factors. 

The role of RKIP in pancreatic beta-cell neogenesis - 

identification of drug targets. 

Similarities between the alternative splicing of TCF7L2 

in mouse and human islets. 

The characterization of math6 promoter sequences 

and regulation by neurog3. 

The identification of wnt9a as a potentially important 

signalling molecule for pancreatic development. 

The identification of and initial work on potential target 

pathways of the bHLH factor math6 during endocrine 



Cell therapy in brittle type 1 diabetes. 

To get a better understanding of the effect of adipokines 

secreted by the visceral tissue on islet beta-cell function 

and in endothelial cells - the effect of treatment. 

To define the relationship between changes in arterial 

pressure, metabolic control of diabetes and endothelial 

dysfunction after gastric bypass in patients with morbid 

obesity. 

Epigenetics and cell differentiation - their role in diabetes 

and obesity. 

To gain insights into the role of hypothalamic microR- 

NAs upon the regulation of whole-body energy and 

glucose homeostasis. 

To determine the molecular targets of sodium tungstate 

that modulate pancreatic beta-cell mass and adipocyte 


To determine whether the different isoforms of TCF7L2 

have different biological effects. 

To determine the biomolecules secreted from adipose 

tissue whose pharmaceutical blockade will prevent the 

development of atherothrombotic dysfunction. 

To perform phenotypic characterization of wnt9a knockout 

embryos. 

To carry out functional studies on math6 target 

pathways. 

Publications 


Altirriba J, Barbera A, Del Zotto H, Nadal B, Piquer S, 

Sánchez-Pla A, Gagliardino JJ, Gomis R. Molecular 

mechanisms of tungstate-induced pancreatic plasticity: 

a transcriptomics approach. BMC Genomics, 10, 


Canals I, Carmona MC, Amigó M, Barbera A, Bortolozzi 

A, Artigas F, Gomis R. A functional leptin system is 

essential for sodium tungstate antiobesity action. 

Endocrinology, 150, 642-650 (2009) 

Carmona MC, Amigó M, Barceló-Batllori S, Julià M, 

Esteban Y, Moreno S, Gomis R. Dual effects of sodium 

tungstate on adipocyte biology: inhibition of adipogenesis 

and stimulation of cellular oxygen consumption. Int 

J Obes (Lond), 33, 534-540 (2009) 

Giménez M, Gilabert R, Conget I. Preclinical atherosclerosis 

in a group of young subjects with type 1 diabetes 

from a Mediterranean area. Med Clin (Barc), 132, 

740-742 (2009) 

Giménez M, Lara M, Jiménez A, Conget I. Glycaemic 

profile characteristics and frequency of impaired 

awareness of hypoglycaemia in subjects with T1D and 

repeated hypoglycaemic events. Acta Diabetol, 46, 

291-293 (2009) 

Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis 

R, Hanefeld M, Jones NP, Komajda M, McMurray JJ; 

RECORD Study Team. Rosiglitazone evaluated for cardiovascular 

outcomes in oral agent combination therapy 

for type 2 diabetes (RECORD): a multicentre, randomised, 

open-label trial. Lancet, 373, 2125-2135 (2009) 


129

Mato E, Lucas M, Petriz J, Gomis R, Novials A. 

Identification of a pancreatic stellate cell population 

with properties of progenitor cells: new role for stellate 

cells in the pancreas. Biochem J, 421, 181-191 (2009) 

Merino I, Borrat X, Balust J, Delgado S, Lacy AM, Vidal 

J, Martinez-Palli G. Rhabdomyolysis after bariatric surgery: 

a potentially fatal complication. Br J Anaesth, 

102, 283-284 (2009) 

Piquer S, Casas S, Quesada I, Nadal A, Julià M, 

Novials A, Gomis R. Role of iduronate-2-sulfatase 

in glucose-stimulated insulin secretion by activation 

of exocytosis. Am J Physiol Endocrinol Metab, 297, 

E793-801 (2009) 

Rueda SF, Fernández C, Nicolau J, Ricart MJ, Esmatjes 

E. Prevalence of cardiovascular risk factors in patients 

with type 1 diabetes in end-stage renal disease: 

changes in the trend from 1999 to 2006. J Diabetes 

Complications, 23, 317-322 (2009) 

Tudurí E, Marroquí L, Soriano S, Ropero AB, Batista 

TM, Piquer S, López-Boado MA, Carneiro EM, Gomis 

R, Nadal A, Quesada I. Inhibitory effects of leptin on 

pancreatic alpha-cell function. Diabetes, 58, 1616-1624 


Vidal J, Nicolau J, Romero F, Casamitjana R, Momblan 

D, Conget I, Morínigo R, Lacy AM. Long-term effects 

of Roux-en-Y gastric bypass surgery on plasma glucagon-like 

peptide-1 and islet function in morbidly obese 

subjects. J Clin Endocrinol Metab, 94, 884-891 (2009) 

Review 

Barceló-Batllori S, Gomis R. Proteomics in obesity research. 

Proteom Clin Appli, 3, 263-278 (2009) 

Conget I, Giménez M. Glucose control and cardiovascular 

disease: is it important? No. Diabetes Care, 32, 

S334-336 (2009) 

















mellitus 


Principal Investigators: Joan J Guinovart, Ramon Gomis, 

Rafael Simó 







Ramon Gomis 






Anna Novials 



Professional training and career development in biomedicine. 

BIOTRACK 

Marie Curie Actions, Co-funding of regional, national 

and international programmes, FP7-PEOPLE-2007-2- 

3-COFUN D: 2009-2012 

Principal Investigator: Ramon Gomis 

Supporting Healthy Lifestyles in the Mediterranean 

Area. FOOD FOR LIFE 

Marie Curie Actions, International Research Staff 

Exchange Scheme, FP7-PEOPLE-IRSES-2008 (230848): 



Project coordinator: Stefano del Prato 

The role of adipose tissue in obesity: beta cell crosstalk. 

ADIBET 

Marie Curie Actions, Industry-Academia Partnerships and 

Pathways, FP7-PEOPLE-2007-3-1-IAPP (218131): 2008-2011 


130 CibeRdem


Transcriptional cascade induced by neurogenin3 in pancreas: 

study of the transcription factors math6 and ebf1 

Ministerio de Ciencia e Innovación, BFU2008-02299/ 

BMC: 2009-2011 

Principal Investigator: Rosa Gasa 

Molecular targets induced by tungstate in obesity 

Ministerio de Educación y Ciencia, SAF2006-07382: 

2006-2011 


Effects of gastric bypass on blood pressure and endothelial 

dysfunction in severely obese subjects 

Ministerio de Sanidad y Consumo, PI070124: 2007-2010 

Principal Investigator: Enric Esmatjes 

Continuous subcutaneous insulin infusion and continuous 

glucose monitoring systems in type 1 diabetes. 

Effect in the cardiovascular risk profile of 

patients with labile control for recurrent and severe 

hypoglycaemia 

Ministerio de Sanidad y Consumo, PI060250: 2006-2009 

Principal Investigator: Ignacio Conget 

Resolving mechanisms of type 2 diabetes after gastric 

bypass in severely obese patients 



Principal Investigator: Josep Vidal 


Experimental Diabetis, cellular and molecular research 

in experimental diabetic models 

Direcció General de Recerca, Generalitat de Catalunya, 

2009 SGR 1426: 2009-2013 


Private funds 

Constitution of a metabolic disease DNA bank 



Pathways involved in the effects of tungstate on the pancreas. 


131


Phase III trial, randomized, double-blind, placebo controlled 

and peer-group to assess the efficacy and safety 

of Linagliptin (5 mg) orally administered once at day for 

more than 52 weeks in type 2 diabetes patients combined 

with insulin as base treatment 

Boehringer Ingelheim: 2009-In progress 

Researcher: Ramon Gomis 

Observational follow-up study of patients prior attended 

in exubera controlled clinical trials. Phase IV 

Pfizer: 2009-In progress 


Phase III study of 24 weeks, international, randomly, 

peer-group, double-blind and placebo controlled with 

an extended period of 24 weeks to assess efficacy and 

safety of dapaglifocin added to treatment of type 2 diabetes 

mellitus patients with poor control of glycaemia 

with insulin 

Astra Zeneca: 2009-2010 


Liraglutide effect compared to Sitagliptine combined 

both with metformin in type 2 diabetes patients. Phase III 

Novo Nordisk Pharma: 2008-In progress 


with altered fasting glucose (AFG), decrease of glucose 

tolerance (TGD) or type 2 diabetes in initial steps. 

Phase IV 

Sanofi-Aventis: 2004-In progress 

Steering Committee Member: Ramon Gomis 


Therapeutical algorism in type 2 diabetes mellitus (2009) 

Grup de Treball Endocrinologia. AIS BCN esquerra 

Author: Enric Esmatjes 

Hiperglycaemia management in hospital patients 


Servei d’Endocrinologia i Nutrició, Hospital Clínic de 

Barcelona 

Author: Enric Esmatjes 

Awards 

«I Boston Scientific Award in Cardiovascular Research 

on Diabetes», Sociedad Española de Diabetes (2009) 

Awardee: Ramon Gomis ■ 

Randomly, double-blind, placebo controlled, peergroups 

and 24 weeks length study to assess efficacy 

and safety of BI1218.15 (5mg) combined with 30mg 

pioglitazone (both orally administered once at day) 

compared to 30mg pioglitazone plus placebo in type 2 

diabetes patients with or without previous treatment experience, 

with insufficient glycaemic control. Phase III 

Boehringer Ingelheim: 2008-2009 


A multicenter, randomized, double-blind clinical trial to 

evaluate the safety and tolerability of 24 weeks treatment 

with vildagliptin (50 mg qd or 100 mg qd) versus 

placebo in patients with type 2 diabetes and moderate 

renal insufficiency. Phase III 

Novartis: 2008-2009 

Researcher: Enric Esmatjes 

Multicenter trial, international, randomized and 2x2 factorial 

to assess the effects of Lantus (glargin insulin) 

compared to the standard treatment with omega 3 fatty 

acids compared to placebo, in the decrease of cardiovascular 

morbility and mortality in high risk patients 

132 CibeRdem

Islet cell and stem cell physiology 

Universidad Pablo de Olavide, Centro Andaluz de Biología Molecular y Medicina Regenerativa, Sevilla 

www.cabimer.es 

Principal Investigator Franz Martín Associate researcher Francisco Bedoya, Genoveva Berná, 

Gladys Cahuana, Remedios Ramirez, Bernat Soria, Juan Tejedo Postdoctoral fellow Anabel Rojas, 

Ángeles de la Torre Ortega PhD student Manuel Carrasco, Andrea Diez Lab technician Raquel 

Araujo, Mario Bautista, Antonio Cárdenas, Ana Belén Hitos, Sergio Mora 

Keywords 

Beta-cell signal transduction. Insulin secretion. Islet degeneration 

and damage. Islet development. Stem cells. 


The group is interested in islet physiology, apoptosis 

and survival. In addition, we study the molecular and 

cellular basis of embryonic and adult stem cells together 

with key steps in islet development. Our latest goal 

is to develop suitable protocols to boost diabetes celltherapy 

clinical trials. 


The study of interactive pathways implicated in 

«Stemness». 

The role of NO in embryonic stem cell differentiation 

and proliferation. 

Transcriptional network operating during pancreas 

development. 

The differentiation of human embryonic stem cells 

(hESCs) to beta-cell like. 

The obtention of IPS and differentiation to beta-cell like. 

The role of endothelial factors in adult islet-cell 

proliferation. 

The regulation of beta-cell survival. 

The development of GMP and clinical trials for diabetes 

cell therapy. 


Islet cell developmental biology. Islet-cell biology. 

Proteomics. Cell signalling. Apoptosis. Stem cells. Cell 

differentiation. Pancreatic islet physiology. Animal transplantation 

studies. Cell therapy clinical trials and GMP. 


The identification of the transcriptional hierarchy among 

GATA4, FoxA2 and PDX1 transcription factors in endoderm 

specification. 

The development of protocols able to increase adult 

islet-cell proliferation without de-differentiation. 

The generation of an IPS cell line able to express eGFP 

under PDX1 and dsRed-1 under insulin. 


133

The establishment of the role of NO in the repression 

of pluripotency genes in embryonic stem cells. 

The initiation of three diabetes cell therapy clinical trials. 


To establish the role of GATA4 in endoderm and pancreas 

development. 

To test the islet-cell proliferation protocol in human 

islets. 

To differentiate the IPS cell line into insulin-secreting 

cells. 

To develop an antibody platform for adult mouse and 

human beta cells. 

To initiate new diabetes cell therapy clinical trials. 

Publications 


Carneiro EM, Latorraca MQ, Araujo E, Beltrá M, 

Oliveras MJ, Navarro M, Berná G, Bedoya FJ, Velloso 

LA, Soria B, Martín F. Taurine supplementation modulates 

glucose homeostasis and islet function. J Nutr 

Biochem, 20, 503-511(2009) 

Fernández-Pachón MS, Berná G, Otaolaurruchi E, 

Troncoso AM, Martín F, García-Parrilla MC. Changes 

in antioxidant endogenous enzymes (activity and gene 

expression levels) after repeated red wine intake. J 

Agric Food Chem, 57, 6578-6583 (2009) 

Rojas A, Schachterle W, Xu SM, Black BL. An endoderm-specific 

transcriptional enhancer from the mouse 

Gata4 gene requires GATA and homeodomain proteinbinding 

sites for function in vivo. Dev Dyn, 238, 2588- 


Todorova MG, Fuentes E, Soria B, Nadal A, Quesada I. 

Lysophosphatidic acid induces Ca2+ mobilization and c- 

Myc expression in mouse embryonic stem cells via the 

phospholipase C pathway. Cell Signal, 21, 523-528 (2009) 

Review 

Hmadcha A, Dominguez-Bendala J, Jane W, Mohamed 

A, Soria B. The immune boundaries for stem cell based 

therapies: problems and prospective solutions. J Cell 

Mol Med, 13, 1464-1475 (2009) 

Book chapter 

Rojas A, Khoo A, Tejedo J, Bedoya FJ, Soria B, Martín F. 

«Islet cell development», in The islet of Langerhans. 

Springer, Advances in Experimental Medicine and 

Biology, 654, 59-75 (2009) 



The production of monoclonal antibodies which selectively 

react with cell surface molecules on human pancreatic 

beta cells 

ANTIBECELL: 2009-2010 

Principal Investigators: Franz Martín, Eduard Montanya, 

Angel Nadal 



Role of GATA4 transcription factor in endoderm and 

pancreas development 

Instituto de Salud Carlos III, PI108/0018: 2009-2011 

Principal Investigator: Anabel Rojas 

Tercel Network 

Instituto de Salud Carlos III, RD06-010: 2007-2010 

Principal Investigator: Bernat Soria 

Molecular characterization of protective action of NO 

on the pancreatic beta-cell 

Ministerio de Educación y Ciencia, SAF-2007-602105: 

2007-2010 

Principal Investigator: Francisco J Bedoya 

Obtention of insulin-secreting cells from human 

monocytes 

Ministerio de Educación y Ciencia, SAF-2006-06673: 


Principal Investigator: Franz Martín 


Role of endothelial factors in the obtention of insulinsecreting 

cells from adult pancreatic ítem cells 

Consejería de Salud, Junta de Andalucía, PI0022/2008: 


Principal Investigator: Franz Martín 

NO regulation of mouse and human beta-cell and pancreatic 

islet survival during the isolation process 

Consejería de Salud, Junta de Andalucía, PI-0095-07: 

2008-2010 

Principal Investigator: Juan R Tejedo 

Characterization of human embryonic stem cell 

markers 

134 CibeRdem

Consejería de Salud, Junta de Andalucía, PI0045/2008: 


Principal Investigator: Juan R Tejedo 

Mechanism of action of beta-lactoglobulin protein in 

type 1 diabetes development 

Universidad Pablo de Olavide, PPI0801: 2008-2009 

Principal Investigator: Ángeles Ortega 


Autologous bone marrow derived mononuclear cells in 

treating diabetic patients with critical limb ischaemia. 

Phase I/II 

IATA (Inicitativa Andaluza de Terapias Avanzadas): 


Researchers: Ruiz R, de la Cuesta A, Soria B, Hmadcha K 

Evaluation of the efficiency and safety of autologous 

bone marrow derived mononuclear cells in treating diabetic 

patients with critical limb ischaemia. Phase I/II 



Researchers: Ruiz R, de la Cuesta A, Soria B, Hmadcha K 

Multicenter, randomized, double blind and placebo-controlled 

clinical trial to evaluate the safety and effectiveness 

of adipose tissue mesenchymal stem cell therapy 

in patients with aggressive multiple sclerosis. Phase I/II 



Researchers: Fernández O, Izquierdo G, Soria B, 

Hmadcha K 

Patents 


Method to differentiate embryonic stem cells towards 

definitive endoderm 


Inventors: Francisco J Bedoya, Juan R Tejedo, Bernat 

Soria, Sergio Mora, Gladys Cahuana, Franz Martín, 

Karim Hmadcha 

UPO-Fundación Progreso y Salud (2009) 

Composition for prevention or treatment of Diabetes 

Mellitus 


Inventors: Francisco Javier Navarro, Franz Martín, 

Patricia Moreno, Verónica Rivero, Elvira León 

UPO-Fundación Progreso y Salud (2009) ■ 

Mouse pancreatic islet showing insulin positive cells with a high 

proliferative rate. 


135

Group of Research into Diabetes and Metabolism 

Hospital Universitari de Bellvitge, Institut d’Investigació Biomèdica de Bellvitge, Universitat de Barcelona 

www.bellvitgehospital.cat 

www.idibell.cat 

www.ub.edu 

Principal Investigator Eduard Montanya Associate researcher José Manuel Gómez, Montserrat 

Nacher, Manuel Pérez, Juan Soler, Nuria Vilarrasa Postdoctoral fellow Noèlia Téllez PhD student 

Jorge Caballero, Géraldine Joanny, Marc Nuñez Lab manager Kelly Roche Lab technician Verónica 

Barceló, Jessica Escoriza 

Keywords 

Gastro-entero pancreatic factors. Islet transplantation. 

Islet degeneration and damage. Stem cells. Weight regulation 

and obesity. 

on the mechanisms of destruction, protection and regeneration 

of pancreatic beta cells with a particular interest in 

the cell therapy of diabetes and in the metabolic and molecular 

regulation of insulin resistance by adipose tissue. 


The reduction in the number of insulin producing beta 

cells is a central aspect in the development of both type 

1 and type 2 diabetes. Thus, the identification of factors 

that lead to the loss of beta cells and the investigation 

of therapeutic interventions aimed at restoring the lost 

beta-cell mass are essential in the search for a cure for 

diabetes. Promising strategies are the transplantation 

of beta cells, the generation of new beta cells by replication 

or neogenesis from pluripotent precursors, and 

the regeneration of the endocrine pancreas. 


The group has two main lines of research: the study of the 

cellular and molecular biology of pancreatic islet cells and 

the study of insulin resistance in obesity. They are focused 


Beta-cell damage by cytokines, inflammatory factors, 

and glucose toxicity. 

Beta-cell regeneration - replication and neogenesis. 

The plasticity and regulation of beta-cell mass. 

The cell therapy of diabetes - islet transplantation. 

The isolation, culture and transplantation of human 

pancreatic tissue. 

Adipokines and insulin resistance in obesity. 

Molecular factors involved in adipogenesis. 

Morbid obesity and bariatric surgery. 

Body composition by impedanciometry and densitometry 

(DEXA). 


The characterization of inflammatory cytokine IL-1beta 

136 CibeRdem

effects on beta-cell replication. 

Innovation in human islet isolation technique leading to 

improved islet quality. 

The characterization of role of glucotoxicity in SNARE 

proteins in insulin exocytosis. 

Successful in vitro expansion of adult pancreatic pluripotent 

cells. 

The characterization of the adipocyte fatty acid-binding 

protein role in insulin sensitivity in morbidly obese 

women. 

The evaluation of gastric bypass effects on bone disease 

in morbidly obese women. 


To characterize the mechanisms of damage and protection 

of transplanted beta cells. 

To further optimize human islet isolation and culture for 

clinical islet transplantation. 

To investigate islet cell regeneration from pancreatic 

adult progenitor cells. 

To define the relationship between adipokines, insulin 

resistance and body composition in obesity. 

To investigate role of adipokines and inflammatory factors 

in insulin resistant obese subjects. 

Publications 


Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya 

E, Brett JH, Zychma M, Blonde L; LEAD-6 Study Group. 

Liraglutide once a day versus exenatide twice a day for 

type 2 diabetes: a 26-week randomised, parallel-group, 

multinational, open-label trial (LEAD-6). Lancet, 374, 

39-47 (2009) 

bone mineral density in morbidly obese women: a 

cross-sectional study in two cohorts before and after 

bypass surgery. Obes Surg, 19, 345-350 (2009) 

Nacher M, Barceló V, Escoriza J, Joanny G, Núñez-Ollé 

M, Montanya E. Optimization of human pancreatic islet 

isolation with a newly designed cooling system for 

COBE 2991. Transplant Proc, 41, 2202-2203 (2009) 

Simón I, Escoté X, Vilarrasa N, Gómez J, Fernández- 

Real JM, Megía A, Gutiérrez C, Gallart L, Masdevall C, 

Vendrell J. Adipocyte fatty acid-binding protein as a determinant 

of insulin sensitivity in morbid-obese women. 


Vilarrasa N, Gómez JM, Elio I, Gómez-Vaquero C, 

Masdevall C, Pujol J, Virgili N, Burgos R, Sánchez- 

Santos R, de Gordejuela AG, Soler J. Evaluation of 

bone disease in morbidly obese women after gastric 

bypass and risk factors implicated in bone loss. Obes 

Surg, 19, 860-866 (2009) 

Review 

Montanya E, Sesti G. A review of efficacy and safety 

data regarding the use of liraglutide, a once-daily human 

glucagon-like peptide 1 analogue, in the treatment of 

type 2 diabetes mellitus. Clin Ther, 31, 2472-2488 (2009) 

Ceperuelo-Mallafré V, Näf S, Escoté X, Caubet E, Gomez 

JM, Miranda M, Chacon MR, Gonzalez-Clemente JM, 

Gallart L, Gutierrez C, Vendrell J. Circulating and adipose 

tissue gene expression of zinc-alpha2-glycoprotein 

in obesity: its relationship with adipokine and lipolytic 

gene markers in subcutaneous and visceral fat. J Clin 

Endocrinol Metab, 94, 5062-5069 (2009) 

Estil·les E, Téllez N, Soler J, Montanya E. High sensitivity 

of beta-cell replication to the inhibitory effects of 

interleukin-1beta: modulation by adenoviral overexpression 

of IGF2 in rat islets. J Endocrinol, 203, 55-63 (2009) 

Gómez JM, Vilarrasa N, Masdevall C, Pujol J, Solano 

E, Soler J, Elio I, Gallart L, Vendrell J. Regulation of 

Human islet showing expression of cytosolic membrane tSNARE 

protein SNAP25 (green) involved in docking of insulin granule in 

the insulin exocytosis process. Beta cells stained for insulin (red), 

and nuclei in blue (confocal microscopy). 


137

Editorial 

Gómez JM, Granada ML, Mauricio D. Endocrinología 

y Nutrición finalmente en Medline. Endocrinol Nutr, 56, 

353-354 (2009) 

Book chapter 

Montanya E, Tellez N. «Pancreatic Remodeling: 

Beta Cell Apoptosis, Proliferation and Neogenesis. 

Measurement of Beta Cell Mass and of Invidual Beta 

Cell Size», in Type 2 Diabetes. Methods and Protocols 

(Methods in Molecular Biology). Humana Press, 560, 

137-158 (2009) 

Montanya E. «Diabetes Mellitus y Terapias poco frecuentes 

o en fase de investigación», in Manual del Residente 

de Endocrinología y Nutrición. SEEN, 903-921 (2009) 





beta cells 



Angel Nadal 





weight loss 




J Vendrell 



Principal Investigator: Eduard Montanya 

Autonomous Community Project 

Consolidated Research Group in Diabetes and 

Metabolism 



Principal Investigator: Eduard Montanya 


Estudio multicéntrico, randomizado, doble ciego, con 

doble enmascaramiento, controlado frente a un comparador 

activo para evaluar la eficacia, seguridad y tolerancia 

de Taspoglutida (RO5073031) comparado con 

pioglitazona en pacientes con diabetes mellitus tipo 2 

controlados inadecuadamente con sulfonilurea (SU) en 

monoterapia o con la combinación metformina más sulfonilurea. 

Phase III 

Hoffmann La Roche: 2009-2011 

Name of the participants: Eduard Montanya, Manuel 

Pérez, Jorge Caballero 

Efecto de Liragltuida en comparación con Sitagliptina, 

ambas en combinación con Metformina en sujetos con 

Diabetes tipo 2. Ensayo de 26 semanas, aleatorio, 

abierto, con comparador activo, de 3 grupos paralelos, 

multicéntrico, multinacional. Phase III 

Novo Nordisk Pharma: 2008-2010 

Name of the participants: Eduard Montanya, Manuel 

Pérez, Jorge Caballero ■ 











Neogenesis of islets of Langerhans from pluripotent 

cells of adult endocrine pancreas 

138 CibeRdem

Unit of Cell Physiology and Nutrition IB-UMH 

Instituto de Bioingeniería, Universidad Miguel Hernández, Elx 

http://diabetes.umh.es 

Principal Investigator Angel Nadal Associate researcher Esther Fuentes, Elena García, Ivan 

Quesada, Cristina Ripoll, Ana Belén Ropero Postdoctoral fellow Paloma Alonso-Magdalena, Sergi 

Soriano, Elaine Vieira PhD student Ernesto Caballero, Marta García-Arévalo, Alejandro González, 

Laura Marroquí, Eva Tudurí Lab technician Pablo Juan-Picó, María Luisa Navarro, Ana Belén Rufete 

Keywords 

Beta-cell signal transduction. Hormone receptors. 

Hormones (non-insulin), action. Insulin secretion. Insulin 

sensitivity and resistance. 


We work on the molecular pathways that regulate the 

secretion and function of alpha, beta and delta cells. We 

also study those conditions leading to their malfunction 

or compromising their survival which are associated with 

diabetes. We study the activation of these molecular 

pathways by different natural and environmental oestrogens, 

studying their implication in glucose homeostasis. 


The role of oestrogen receptors in the physiology of 

the islet of Langerhans, the study of the actions of oestrogens 

and xenooestrogens in pancreatic alpha and 

beta cells. We have a particular interest in the role of 

xenooestrogens in the aetiology of type 2 diabetes. 

Signal transduction pathways involved in the function of 

alpha, beta and delta cells. We study the activation of 

signalling pathways by leptin receptors and its consequences 

in insulin and glucagon secretion. 

The role of ANP (atrial natriuretic peptide) receptors 

in beta-cell function and blood glucose homeostasis. 

ANP is increased in cardiovascular pathologies which 

in many cases are associated with insulin resistance 

syndrome. We are working to understand the role of 

ANP receptors in the endocrine pancreas. 


Stimulus secretion coupling in alpha, beta and delta 

cells; we use electrophysiology as well as fluorescence 

microscopy to analyse stimulus secretion coupling in response 

to hormones and nutrients in health and disease. 

In combination with appropriate fluorescent sensors, 

imaging techniques allow on-line and dynamic analysis 

of multiple cellular and physiological parameters. 

Electrophysiological techniques permit us to understand 

the role of ion channels in the different types of 

cells within the islet. RIA and ELISA are used for insulin 

secretion experiments. 


139


In 2009 we have been able to describe the existence 

and function of leptin receptors in alpha cells of mice 

and human islets. We have unveiled the role of the oestrogen 

receptor ER-beta in the rapid regulation of ATPsensitive 

K+ channels and insulin secretion. 

Our group has also shown the role of cannabinoid receptors 

in alpha and beta cells and has demonstrated 

that PPAR-alpha ligands modulate calcium signals and 

insulin secretion in pancreatic beta cells. 


In the future, we aim to establish the role that ERalpha 

and ER-beta have on glucose homeostasis and 

the role of the environmental hormone, bisphenol-A 

in the aetiology of type 2 diabetes. In addition, we 

will continue working to understand how stimulus secretion 

coupling works in pancreatic alpha cells and 

how adipocyte-releasing hormones affect it. We plan 

to investigate the role of the ANP receptor in the islet 

of Langerhans. 

Publications 


Piquer S, Casas S, Quesada I, Nadal A, Julià M, 

Novials A, Gomis R. Role of iduronate-2-sulfatase 

in glucose-stimulated insulin secretion by activation 

of exocytosis. Am J Physiol Endocrinol Metab, 297, 

E793-801 (2009) 

Ropero AB, Juan-Picó P, Rafacho A, Fuentes E, 

Bermúdez-Silva FJ, Roche E, Quesada I, de Fonseca 

FR, Nadal A. Rapid non-genomic regulation of Ca2+ 

signals and insulin secretion by PPAR alpha ligands in 

mouse pancreatic islets of Langerhans. J Endocrinol, 

200, 127-138 (2009) 

Soriano S, Ropero AB, Alonso-Magdalena P, Ripoll 

C, Quesada I, Gassner B, Kuhn M, Gustafsson JA, 

Nadal A. Rapid regulation of K(ATP) channel activity 

by 17{beta}-estradiol in pancreatic {beta}-cells involves 

the estrogen receptor {beta} and the atrial natriuretic 

peptide receptor. Mol Endocrinol, 23, 1973-1982 


Todorova MG, Fuentes E, Soria B, Nadal A, Quesada I. 

Lysophosphatidic acid induces Ca2+ mobilization and c- 

Myc expression in mouse embryonic stem cells via the 

phospholipase C pathway. Cell Signal, 21, 523-528 (2009) 

Tudurí E, Marroquí L, Soriano S, Ropero AB, Batista TM, 

Piquer S, López-Boado MA, Carneiro EM, Gomis R, 

Nadal A, Quesada I. Inhibitory effects of leptin on pancreatic 

alpha-cell function. Diabetes, 58, 1616-1624 (2009) 

Review 

Nadal A, Alonso-Magdalena P, Soriano S, Ropero AB, 

Quesada I. The role of estrogens in the adaptation of 

islets to insulin resistance. J Physiol, 587, 5031-5037 


Bermúdez-Silva FJ, Suarez-Pérez J, Nadal A, 

Rodríguez de Fonseca F. The role of pancreatic endocannabinoid 

system in glucose metabolism. Best Pract 

Res Clin Endocrinol Metab, 23, 87-102 (2009) 

Nadal A, Alonso-Magdalena P, Soriano S, Quesada I, 

Ropero AB. The pancreatic beta-cell as a target of estrogens 

and xenoestrogens: implications for blood glucose 

homeostasis and diabetes. Mol Cell Endocrinol, 

304, 63-68 (2009) 

Editorial 

Myers JP, vom Saal F, Akingbemi BT, Arizono K, 

Belcher S, Colborn T, Chahoud I, Crain DA, Farabolli 

F, Guillete Jr LJ, Hassold T, Ho S, Hunt PA, Iguchi T, 

Jobling S, Kanno J, Laufer H, Marcus M, McLachlan JA, 

Nadal A, Oelhmann J, Olea N, Palanza P, Parmigiani S, 

Rubin BS, Schoenfelder G, Sonneschein C, Soto AM, 

Talsness CE, Taylor JA, Venderberg LN, Vanderbergh 

JG, Vogel S, Watson CS, Welshons WV, Zoeller RT. 

Why public health agencies cannot depend on good 

laboratory practices as a criterion for selecting data: 

the case of bisphenol A. Environ Health Perspect, 117, 

309-315 (2009) 





beta cells 



Angel Nadal 



Circadian regulation in the control of insulin and glucagon 

release and its role in Type 2 diabetes 

European Commission, Programme PEOPLE, PIEF- 

140 CibeRdem

GA-2009-234879: 2009-2011 

Principal Investigator: Ivan Quesada 


Efectos a corto y largo plazo de la activación de los 

receptores de estrógenos sobre el contenido, la secreción 

y la supervivencia de la célula-beta pancreática 



Principal Investigator: Angel Nadal 

Efecto de la leptina sobre la expresión y secreción de 

glucagón y sobre la plasticidad del páncreas endocrino 

Ministerio de Educación y Ciencia, BFU2007-67607: 

2007-2010 

Principal Investigator: Ivan Quesada 

Autonomous Community Project 

Implicación de las guanilato ciclasas de membrana en 

la función del páncreas endocrino 

Conselleria d’Educació, Generalitat Valenciana, 

GV/2009/56: 2009-2010 

Principal Investigator: Ana Belén Ropero 

Private Funds 

Papel de los péptidos natriuréticos en el síndrome 

metabólico. Estudio sobre la homeostasis de la glucosa 

UMH-Bancaja, IP/WY/01: 2009-2010 

Principal Investigator: Ana Belén Ropero ■ 

Mitochondria of several cells within an islet stained with 

Mitotracker®. 

3D projection of an islet with alpha cells stained in green and 

beta cells in red. 


141

Metabolic and molecular disturbances in diabetes 


www.diabetisiobesitat.org 

Principal Investigator Anna Novials Associate researcher Joan Marc Servitja Postdoctoral 

fellow Paola Casini, Maud Soty PhD student Laura Brugnara, Lisa Cadavez, Alba Moreno, Montse 

Visa Lab technician Carlos Castaño Nutritionist Serafín Murillo 

Keywords 

Genomics. Endothelium. Exercise. Islet amyloid polypeptide/amylin. 

Islet degeneration and damage. 


Our group focuses its research on investigating the 

molecular and environmental mechanisms critical for 

pancreatic beta-cell dysfunction in type 2 diabetes. Our 

expertise in pancreatic islets has been useful in allowing 

us to describe some molecular mechanisms related 

to beta-cell toxicity and apoptosis, in particular those 

related to amyloidogenesis. In addition, our expertise 

in the clinical setting is important in understanding the 

molecular and metabolic mechanism induced by exercise 

as a critical environmental factor involved in the 

prevention and treatment of diabetes. 


Mechanisms of amyloidogenesis of the pancreatic beta-cell 

- the role of mitochondrial function and protein 

folding. 

The effect of peripheral amylin on the endothelial 

function. 

How signalling pathways modulate the transcriptional 

programme in pancreatic beta cells under different 

physiological and stress conditions. 

The role of glucose in epigenetic and metabolic changes 

in the pancreatic beta-cell. 

The effect of different exercise programmes on metabolic 

and molecular markers in patients affected by 

diabetes. 


The group has developed different lines of expertise 

related to both basic and clinical research. Basic expertise 

includes the following: the isolation of human, 

rat and mouse pancreatic islets including secretory and 

morphometry analysis; the establishment of stable cellular 

lines; lentiviral infection of pancreatic islets and 

cellular lines; mitochondrial respiration and the activity 

of pancreatic islets and cell lines; genomic and epigenetic 

analysis of pancreatic islets - microRNA analysis 

and genome-wide maps of transcription factor binding 

142 CibeRdem

and histone marks to study transcriptional regulatory 

networks; and functional studies in animals including 

clamp techniques, exercise tests and indirect calorimetry 

for the analysis of metabolic consumption rate. 

Our clinical expertise in humans includes: the assessment 

of fitness and exercise capacity (resting metabolic 

rate by indirect calorimetry); body composition analysis 

by DEXA; aerobic capacity (VO2 max) by exercise 

tests and muscular strength capacity; and the assessment 

of endothelial function including endothelial pulse 

wave analysis (Endo-Pat) and measurement of carotid 

intimae-media by echography. 


In 2009 the group published research results relating to 

the role of the enzyme iduronate sulfatase (IDS) in the 

pancreatic beta-cell. We demonstrated that this particular 

enzyme is involved in the machinery of insulin 

exocytosis. 

After several years of research, the group has also 

identified and published one specific pancreatic cell 

population named stellate cells. These cells have the 

properties of progenitor cells and may have the capacity 

to express and produce insulin. Studies are in progress 

to further analyse and characterize the secretome 

of these cells. These cells offer a new perspective in 

the treatment of diabetes. 

The clinical team of the group has set up the unit of clinical 

research where patients are phenotyped. We focus 

particularly on the assessment of fitness and exercise capacity, 

body composition, metabolic consumption, clamp 

techniques and the analysis of endothelial function. 


Our proposal is to understand some of the mechanisms 

involved in beta-cell dysfunction in type 2 diabetes. 

We are interested in the process relating to pancreatic 

amyloidogenesis as a result of amylin fibril formation. 

We will focus our attention on investigating the effect of 

the amylin peptide in mitochondrial function, ER stress 

response and the process of protein folding. 

We also are interested in identifying the transcriptional networks 

and epigenetic mechanisms underlying the control 

of gene expression by glucose and hypoxia in pancreatic 

islets. In addition, we would like to identify the microRNAs 

regulated by specific stimuli in pancreatic islets. 

On the clinical side, we intend to develop two different 

projects. Firstly, we will analyse the metabolic changes 

induced by acute and chronic exercise in the diabetic 

population. Secondly, we are interested in correlating 

the effect of peripheral amylin levels on endothelial 

function in the diabetic population. 

Publications 


Mato E, Lucas M, Petriz J, Gomis R, Novials A. 

Identification of a pancreatic stellate cell population 

with properties of progenitor cells: new role for stellate 

cells in the pancreas. Biochem J, 421, 181-191 (2009) 

Piquer S, Casas S, Quesada I, Nadal A, Julià M, Novials 

A, Gomis R. Role of iduronate-2-sulfatase in glucosestimulated 

insulin secretion by activation of exocytosis. 

Am J Physiol Endocrinol Metab, 297, E793-801 (2009) 













Anna Novials 



The role of Bace enzime (beta-site amyloid precursor 

protein cleaving enzyme) in pancreatic islet function 



Principal Investigator: Anna Novials 

Design, characterization and follow-up of trainings addressed 

to produce metabolic improvements in type 2 

diabetic patients 

Ministerio de Ciencia e Innovación, DPS2008-06922: 

2008-2011 


Project coordinator: Joan Aureli Cadefau 

Study of the response of pancreatic islet to hypoxia: 

role of HIF-1 


143

Ministerio de Educación y Ciencia, BFU2006-09072: 


Principal Investigator: Joan Marc Servitja 

Private funds 

Constitution of a metabolic disease DNA bank 



Parámetros de riesgo para la aparición y el desarrollo 

del edema macular en el paciente diabético: Validación 

de perfiles de riesgos metabólicos y genéticos 

Fundación para la Diabetes: 2009 



Multicenter trial, international, randomized and 2x2 factorial 

to assess the effects of Lantus (glargin insulin) 

compared to the standard treatment with omega 3 fatty 

acids compared to placebo, in the decrease of cardiovascular 

morbility and mortality in high risk patients 

with altered fasting glucose (AFG), decrease of glucose 

tolerance (TGD) or type 2 diabetes in initial steps. 

Phase IV 

Sanofi-Aventis: 2004-In progress 

Researcher: Anna Novials ■ 

Characterization of pancreatic stellate cell clusters. The first, top 

left, panel (a) shows a representative cell cluster after treatment 

with M 3. The markers are visualized as follows: in red, C-peptide; 

in green, insulin, vimentin, CK 19, GFAP and alpha-actin; merges 

appear yellow. The insulin-secreting mouse pancreatic beta-cell 

line MIN-6 was used as the immunohistochemical control. 

144 CibeRdem

Transcriptional mechanisms of pancreatic function 

Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas, 

Universidad Autónoma de Madrid 

www.iib.uam.es 

Principal Investigator Mario Vallejo Postdoctoral fellow María Natacha Díaz, Mercedes Mirasierra 

PhD student Patricia García, Laura Ruiz Lab manager Antonio Fernández 

Keywords 

Insulin synthesis. Islet degeneration and damage. Islet 

development. Transcription factors. 


We study the role of transcription factors that regulate 

the development and function of pancreatic beta cells. 

We are focusing mainly on the homeoprotein Alx3 and 

are investigating why Alx3 deficiency leads to defects 

in insulin secretion, impaired beta-cell survival and altered 

glucose homeostasis. Alx3 is also expressed in 

the developing central nervous system, and therefore 

we investigate whether Alx3 deficiency constitutes an 

increased risk of congenital neural defects associated 

with diabetes. 


The characterization of phenotypic alterations of pancreatic 

islets in the absence of Alx3. 

The requirement of Alx3 for the maintenance of glucose 

homeostasis in vivo. 

The identification of transcriptional targets regulated by 

Alx3. 

The determination of the expression pattern of Alx3 

during pancreas development. 

The role of Alx3 in the regulation of the development 

of the neural tube and vulnerability to hyperglycaemic 

insult in its absence. 


From a molecular biology point of view, we investigate 

transcriptional mechanisms in which Alx3 participates, 

attempting to discover relevant target genes regulated 

by Alx3. From a cell biology point of view, we study the 

influence of Alx3 on the maintenance of phenotypic 

cell stability in islets. Finally, from the perspective of the 

whole organism, we investigate the role of Alx3 in the 

maintenance of glycaemic homeostasis and in the protection 

of the embryo against hyperglycaemia. 


In 2009 we defined the main phenotypic features of 


145

Alx3 deficiency. Alx3 knockout mice exhibit hyperglycaemia 

and impaired glucose tolerance, a reduction 

in the pancreatic expression of glucokinase, insulin 

and glucagon, as well as alterations in the cellular 

distribution in islets, which show increased apoptosis 

and reduced size. In addition, we developed a 

model of gestational diabetes in mice to evaluate 

the risk of congenital malformations in the absence 

of Alx3. The main findings of these two studies have 

recently been submitted for publication in specialist 

journals. 


To identify target genes regulated by Alx3 that may be 

important for normal pancreatic islet development and 

function. 

To determine the molecular mechanisms that regulate 

Alx3 expression in islets. 

To determine the mechanisms by which Alx3 deficiency 

increases vulnerability of the developing embryo to hyperglycaemic 

insult. 

To establish collaborative studies to investigate whether 

mutations in the Alx3 gene increase predisposition to 

diabetes in humans. 

Publications 

Review 

Vallejo M. PACAP signaling to DREAM: a cAMP-dependent 

pathway that regulates cortical astrogliogenesis. 

Mol Neurobiol, 39, 90-100 (2009) 






humans 












A pleiotropic role for the homeoprotein Alx3 on the 

maintenance of cell viability and survival 



Principal Investigator: Mario Vallejo 

Patents 


Stem cells of the islets of Langerhans and their use in 

treating diabetes mellitus 

Patent application number: 11/410412, US 7544510 

Inventors: Habener J, Abraham E, Zulewski H, Thomas 

MK, Vallejo M 

The General Hospital Corporation (Massachusetts 

General Hospital, Boston) (2009) ■ 

Immunofluorescence images taken by confocal microscopy from 

a pancreas section from an Alx3-deficient mouse processed for 

somatostatin (green) or insulin (red). Note the altered distribution 

of somatostatin-expressing cells, which are not confined to the 

periphery of the islet, and the anomalous coexpression of somatostatin 

and insulin in some cells. Panels on the bottom depict 

higher magnification images of the areas indicated by a square 

in the top panels. Examples of cells expressing only somatostatin 

(asterisks), only insulin (arrows) or both somatostatin and insulin 

(arrowheads) are indicated. 

146 CibeRdem

Epilogue

Principal Investigator index 

Álvarez, Carmen . .......................................................................108 

Balsinde, Jesús . .........................................................................68 

Benito, Manuel . ..........................................................................42 

Blanco, Francisco . .......................................................................71 

Blázquez, Enrique . ......................................................................110 

Bosch, Fàtima . .........................................................................113 

Burks, Deborah . ........................................................................116 

Carmena, Rafael . ........................................................................74 

Castaño, Luis . ..........................................................................119 

Correig, Xavier . ..........................................................................44 

de Pablo, Flora . ........................................................................123 

Escobar Morreale, Héctor F . ...............................................................77 

Ferrer, Jorge . ..........................................................................125 

Gómez Foix, Anna Maria . ..................................................................47 

Gomis, Ramon . .........................................................................128 

Guinovart, Joan J . .......................................................................50 

Ibáñez, Lourdes . .........................................................................80 

Lorenzo, Margarita . .......................................................................53 

Martín, Franz . ..........................................................................133 

Martínez Valverde, Ángela . ................................................................57 

Masana, Lluís . ..........................................................................84 

Montanya, Eduard . ......................................................................136 

Nadal, Angel . ..........................................................................139 

Novials, Anna . .........................................................................142 

Serrano Ríos, Manuel . ....................................................................87 

Simó, Rafael . ...........................................................................90 

Soriguer, Federico . .......................................................................95 

Vallejo, Mario . ..........................................................................145 

Vázquez-Carrera, Manuel . .................................................................98 

Vendrell, Joan J . ........................................................................101 

Villanueva-Peñacarrillo, María Luisa . .........................................................60 

Zorzano, Antonio . ........................................................................62 


149

Keyword index * 

Beta-cell signal transduction 42, 108, 113, 116, 133, 

139 

Bioinformatics . ............................ 44 

Biomarkers and Imaging . ................. 77, 84 

Carbohydrate metabolism . ................ 47, 50 

Catecholamines . .......................... 123 

Clinical diabetes . .................. 90, 119, 128 

Cytokines . ................. 42, 53, 57, 68, 77, 80 

Endothelium . ...................... 84, 128, 142 

Epidemiology . .......................... 87, 95 

Exercise . .......................... 53, 62, 142 

Gastro-entero pancreatic factors . ............. 136 

Gene therapy . ............................ 113 

Genetics type 1 diabetes . ................... 119 

Genetics type 2 diabetes . ......... 71, 87, 110, 125 

Genomics . .................... 62, 87, 125, 142 

Glucose transport . ...................... 53, 60 

Hormone receptors . ......... 57, 60, 110, 123, 139 

Hormones (non-insulin), action . .............. 139 

Immunology (clinical) . ...................... 119 

Incretins . ............................. 60, 110 

Insulin action . ...................... 57, 62, 108 

Insulin secretion . ...................... 133, 139 

Insulin sensitivity and resistance 42, 47, 50, 53, 57, 60, 

62, 74, 77, 80, 98, 101, 108, 113, 116, 139 

Insulin synthesis . ......................... 145 

Insulin therapy . ............................ 95 

Islet amyloid polypeptide/amylin . ............. 142 

Islet degeneration and damage 116, 128, 133, 136, 

142, 145 

Islet development. . . 42, 108, 123, 125, 128, 133, 145 

Islet transplantation . ....................... 136 

Lipid metabolism 44, 47, 53, 60, 68, 71, 74, 84, 90, 98 

Lipid signalling . ............................ 68 

Lipids, lipoproteins . ................ 44, 71, 84, 98 

Macrovascular disease . ............... 42, 74, 84 

Metabolic syndrome 50, 68, 71, 74, 80, 87, 90, 95, 98, 

101 

Metabolomics . ............................ 44 

Neuropathy-somatic . ...................... 113 

Oral pharmacological agents . ............. 50, 119 

Paediatrics . ............................... 80 

Pathogenic mechanisms . .................... 71 

Phospholipases . ........................... 68 

Polycystic ovary syndrome . .................. 77 

Prediction/prevention of type 1 diabetes . ....... 119 

Prediction/prevention of type 2 diabetes . .... 95, 101 

Pregnancy . .......................... 101, 108 

Prevention of type 2 diabetes . ................ 80 

Proinsulin . ............................... 123 

Proteomics . ............................ 77, 87 

Retinopathy . ................ 50, 57, 90, 113, 116 

Stem cells . .................. 110, 116, 133, 136 

Transcription factors . ........ 62, 98, 123, 125, 145 

Weight regulation and obesity 57, 74, 90, 95, 101, 110, 

128, 136 

*Source: DIAMAP, Road Map for Diabetes Research in Europe. 


151

Original articles index 

With CIBERDEM affiliation 

Altirriba J, Barbera A, Del Zotto H, Nadal B, Piquer S, Sánchez-Pla A, Gagliardino JJ, Gomis R. Molecular mechanisms 

of tungstate-induced pancreatic plasticity: a transcriptomics approach. BMC Genomics, 10, 406 (2009) 

Boj SF, Servitja JM, Martin D, Rios M, Talianidis I, Guigo R, Ferrer J. Functional targets of the monogenic diabetes 

transcription factors HNF-1alpha and HNF-4alpha are highly conserved between mice and humans. Diabetes, 58, 

1245-1253 (2009) 

Broch M, Auguet MT, Ramírez R, Olona M, Aguilar C, Megia A, Alcaide MJ, Pastor R, Martínez S, Caubet E, 

Garcia-España A, Richart C. Parallel downregulation of retinol-binding protein-4 and adiponectin expression in 

subcutaneous adipose tissue of non-morbidly obese subjects. Eur J Endocrinol, 161, 87-94 (2009) 

Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, Zychma M, Blonde L; LEAD-6 Study Group. 

Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, 

multinational, open-label trial (LEAD-6). Lancet, 374, 39-47 (2009) 

Caixàs A, Tirado R, Vendrell J, Gallart L, Megía A, Simón I, Llauradó G, González-Clemente JM, Giménez-Palop 

O. Plasma visfatin concentrations increase in both hyper and hypothyroid subjects after normalization of thyroid 

function and are not related to insulin resistance, anthropometric or inflammatory parameters. Clin Endocrinol 


Canals I, Carmona MC, Amigó M, Barbera A, Bortolozzi A, Artigas F, Gomis R. A functional leptin system is essential 

for sodium tungstate antiobesity action. Endocrinology, 150, 642-650 (2009) 

Cardona F, Guardiola M, Queipo-Ortuño MI, Murri M, Ribalta J, Tinahones FJ. The -1131T>C SNP of the APOA5 

gene modulates response to fenofibrate treatment in patients with the metabolic syndrome: a postprandial study. 


Carmona MC, Amigó M, Barceló-Batllori S, Julià M, Esteban Y, Moreno S, Gomis R. Dual effects of sodium tungstate 

on adipocyte biology: inhibition of adipogenesis and stimulation of cellular oxygen consumption. Int J Obes 

(Lond), 33, 534-540 (2009) 

Carneiro EM, Latorraca MQ, Araujo E, Beltrá M, Oliveras MJ, Navarro M, Berná G, Bedoya FJ, Velloso LA, Soria 

B, Martín F. Taurine supplementation modulates glucose homeostasis and islet function. J Nutr Biochem, 20, 

503-511(2009) 


153

Chacón MR, Ceperuelo-Mallafré V, Maymó-Masip E, Mateo-Sanz JM, Arola L, Guitiérrez C, Fernandez-Real JM, 

Ardèvol A, Simón I, Vendrell J. Grape-seed procyanidins modulate inflammation on human differentiated adipocytes 

in vitro. Cytokine, 47, 137-142 (2009) 

Escobar-Morreale HF, Luque-Ramírez M, San-Millán JL. Serum visceral adipose tissue-derived serine protease 

inhibitor concentrations in human obesity and polycystic ovary syndrome. Diabetes Care, 32, e6 (2009) 

Escribano O, Guillén C, Nevado C, Gómez-Hernández A, Kahn CR, Benito M. Beta-Cell hyperplasia induced by 

hepatic insulin resistance: role of a liver-pancreas endocrine axis through insulin receptor A isoform. Diabetes, 

58, 820-828 (2009) 

Estil·les E, Téllez N, Soler J, Montanya E. High sensitivity of beta-cell replication to the inhibitory effects of 

interleukin-1beta: modulation by adenoviral overexpression of IGF2 in rat islets. J Endocrinol, 203, 55-63 (2009) 

Fernández-Millán E, Gangnerau MN, De Miguel-Santos L, Calderari S, Serradas P, Escrivá F, Portha B, Alvarez 

C. Undernutrition of the GK rat during gestation improves pancreatic IGF-2 and beta-cell mass in the fetuses. 

Growth Factors, 27, 409-418 (2009) 

Fernández-Pachón MS, Berná G, Otaolaurruchi E, Troncoso AM, Martín F, García-Parrilla MC. Changes in antioxidant 

endogenous enzymes (activity and gene expression levels) after repeated red wine intake. J Agric Food 

Chem, 57, 6578-6583 (2009) 

Fernández-Veledo S, Vila-Bedmar R, Nieto-Vazquez I, Lorenzo M. c-Jun N-terminal kinase 1/2 activation by tumor 

necrosis factor-alpha induces insulin resistance in human visceral but not subcutaneous adipocytes: reversal by 

liver X receptor agonists. J Clin Endocrinol Metab, 94, 3583-3593 (2009) 

García-Arumí J, Fonollosa A, Macià C, Hernandez C, Martinez-Castillo V, Boixadera A, Zapata MA, Simo R. 

Vitreous levels of erythropoietin in patients with macular oedema secondary to retinal vein occlusions: a comparative 

study with diabetic macular oedema. Eye (Lond), 23, 1066-1071 (2009) 

Garcia-Ramírez M, Hernández C, Villarroel M, Canals F, Alonso MA, Fortuny R, Masmiquel L, Navarro A, García- 

Arumí J, Simó R. Interphotoreceptor retinoid-binding protein (IRBP) is downregulated at early stages of diabetic 

retinopathy. Diabetologia, 52, 2633-2641 (2009) 

Garrido-Sánchez L, García-Fuentes E, Cardona F, Rojo-Martínez G, Soriguer F, Tinahones FJ. Anti-oxidized LDL 

antibody levels are reduced in women with hypertension. Eur J Clin Invest, 39, 800-806 (2009) 

Gauthier BR, Wiederkehr A, Baquié M, Dai C, Powers AC, Kerr-Conte J, Pattou F, MacDonald RJ, Ferrer J, 

Wollheim CB. PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM 

suppression. Cell Metab, 10, 110-118 (2009) 

Gómez JM, Vilarrasa N, Masdevall C, Pujol J, Solano E, Soler J, Elio I, Gallart L, Vendrell J. Regulation of bone 

mineral density in morbidly obese women: a cross-sectional study in two cohorts before and after bypass surgery. 


González-Muñoz E, López-Iglesias C, Calvo M, Palacín M, Zorzano A, Camps M. Caveolin-1 loss of function 

accelerates glucose transporter 4 and insulin receptor degradation in 3T3-L1 adipocytes. Endocrinology, 150, 

3493-3502 (2009) 

González-Rodriguez A, Alba J, Zimmerman V, Kozma SC, Valverde AM. S6K1 deficiency protects against apoptosis 

in hepatocytes. Hepatology, 50, 216-229 (2009) 

154 CibeRdem

Gubern A, Barceló-Torns M, Barneda D, López JM, Masgrau R, Picatoste F, Chalfant CE, Balsinde J, Balboa MA, 

Claro E. JNK and ceramide kinase govern the biogenesis of lipid droplets through activation of group IVA phospholipase 

A2. J Biol Chem, 284, 32359-32369 (2009) 

Gubern A, Barceló-Torns M, Casas J, Barneda D, Masgrau R, Picatoste F, Balsinde J, Balboa MA, Claro E. Lipid 

droplet biogenesis induced by stress involves triacylglycerol synthesis that depends on group VIA phospholipase 

A2. J Biol Chem, 284, 5697-5708 (2009) 

Guitart M, Andreu AL, García-Arumi E, Briones P, Quintana E, Gómez-Foix AM, García-Martínez C. FATP1 localizes 

to mitochondria and enhances pyruvate dehydrogenase activity in skeletal myotubes. Mitochondrion, 9, 

266-272 (2009) 

Haurigot V, Villacampa P, Ribera A, Llombart C, Bosch A, Nacher V, Ramos D, Ayuso E, Segovia JC, Bueren JA, 

Ruberte J, Bosch F. Increased intraocular insulin-like growth factor-I triggers blood-retinal barrier breakdown. J 

Biol Chem, 284, 22961-22969 (2009) 

Hernández C, Rodríguez B, Losada E, Corraliza L, García-Ramírez M, Simó R. Normoalbuminuric type 1 diabetic 

patients with retinopathy have an impaired tubular response to desmopressin: its relationship with plasma endothelin-1. 


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161

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Luisa Mansego | Margarita Lorenzo group | Jesús Martín | Juan Martín | Eugènia Mato | Jordi Merino | Jordi Mesa | Metabolomics Platform | 

Marta Montori | Juan Pablo Muñoz | Cayetana Murillo | Luke Noon | Bernardo Nuche-Berenguer | Vanesa Pérez | Miguel Ángel Rodríguez | 

Octavi Rodríguez | Gemma Rojo | Isabel Roncero | Ana Belén Ropero | Susana Ros | Jesús Ruberte | Juan Miguel Ruiz-Albusac | María del 

Carmen Sanz | Manuel Serrano Ríos | Servei de Mitjans Audiovisuals de l’Hospital Sant Joan de Déu | Raimon Solà | Unitat d’Audiovisuals de 

l’Hospital Universitari de Bellvitge | Ricardo Uña | Mario Vallejo | Patricia Vázquez | Manuel Vázquez-Carrera | Esther Velázquez | Laia Vilà | 

Rocío Vila | Marta Villarroel | Maria Vinaixa | Carina Zabena 

© Cover image Age Fotostock/Steve Gschmeissner/SC/Science Photo Library Pancreatic cells coloured transmission electron 

micrograph TEM of an acinar exocrine pancreatic cell blue adjacent to an hormone- secreting endocrine Islet of Langerhans 

cell green acinar cells secrete zymogens inactive digestive enzymes in vesicles called zymogen granules large purple blobs, left, 

which then become activated when in the small intestine Islet of Langerhans cells regulate blood sugar levels by secreting hormones 

such as insulin and glucagon, that are also transported out of the cell by granules small blue dots, right. The large orange 

bodies centre right and top right are nuclei and the small brown organelles seen throughout are mitochondria. 

Special thanks to all those individuals and institutions without whose cooperation and good will this book would not have been possible.

Biomedical research demands an on-going evaluation that serves as an indicator of the level of excellence 

attained using the resources that public and private entities devote to subsidizing research projects. 

CIBERDEM, the Spanish Biomedical Research Centre (CIBER) in Diabetes and Associated Metabolic 

Disorders, is not immune to this process; on the contrary, for a public research institution, these demands 

are even greater. In this sense, the present Annual Report is a mirror which reflects the scientific outputs 

and outcomes of CIBERDEM and is therefore essential to the continued evaluation of the research groups 

that comprise this CIBER. Ramon Gomis, CIBERDEM Scientific Director

2009 AnnuAl RepoRt 2009 AnnuAl RepoRt - Ciberdem

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