2011 ADA Posters 1261-2041.indd - Diabetes

Integrated Physiology/
Obesity
POSTERS
1787-P
Implication of Corticotropin-Releasing-Hormone on INS-1 and Pancreatic
Islets In Vitro
BARBARA LUDWIG, JANINE SCHMID, CHRISTIAN ZIEGLER, MONIKA EHRHART-
BORNSTEIN, STEFAN R. BORNSTEIN, Dresden, Germany
Hormonal factors, including corticotropin-releasing-hormone (CRH) and
glucocorticoids (GC) regulate the activity of the hypothalamic-pituitaryadrenal
(HPA) axis in response to stress. This axis is kept in balance by
the negative feedback effects of GC on the CRH synthesis and secretion
in the hypothalamus. Recently CRH has been identifi ed to promote β-cell
proliferation and potentiates insulin secretion in a glucose dependent
manner. On the other hand, GCs are referred to as diabetogenic hormones
due to the induction of gluconeogenesis, implication on development of
insulin resistance, effects on adipocytes and the functionally insulinantagonizing
effects. Therefore, an imbalance of the CRH/GC system may
lead to metabolic dysfunction and diabetes.
GC access to intracellular receptors is regulated by two isoforms
of 11β-hydroxysteroid dehydrogenase (11β-HSD) which catalyse the
interconversion of physiologically active GC to its inactive metabolite
(11β-HSD-2) and vice versa (11β-HSD-1).
In the present study we analyzed the mechanism of CRH mediated
β-cell regulation and asked if pancreatic islets respond directly to CRH by
interference with 11β-HSD activity and therefore GC activity.
In in vitro studies we could demonstrate that CRH and its receptor are
expressed on mRNA and protein levels in INS-1 cells, rat and human islets.
We also found expression of both 11β-HSD isoforms in rat and human
islets. CRH exposure of islets signifi cantly decreased mRNA levels of
both 11β-HSD-isoforms as measured by quantitative RT-PCR. The specifi c
iso-enzyme activity was analyzed by measuring the production of active
GC. Following CRH treatment, active GC levels were signifi cantly reduced
indicating an overbalance in favour of 11β-HSD-2 activity. Stimulation with
CRH resulted in signifi cantly increased insulin secretion. Moreover, CRHreceptor
activation caused a signifi cant increase of cell proliferation and
reduced cell apoptosis.
We suggest that CRH may not only be of signifi cance within the
endocrine stress system for triggering and sustaining obesity and metabolic
dysfunction, but may also play a direct role for glucose homoeostasis and
the regulation of β-cell mass.
1788-P
Improved Glycemic Control Enhances the Incretin Effect in Patients
with Type 2 Diabetes
ZHIBO AN, SADIA ALI, COLLEEN ROGGE, FAY HAILES, CATHY BAILEY, BRENDA
WENSTRUP, BRIANNE REEDY, MARZIEH SALEHI, DAVID A. D’ALESSIO, Cincinnati, OH
The incretin effect is impaired in type 2 diabetes, and diabetic subjects have
diminished responses to incretins. However, it is not clear whether the defects
are specifi c for incretin stimulated insulin secretion or simply another aspect of
generalized β-cell dysfunction. Correction of chronic hyperglycemia improves
incretin action in animals. Further, normalization of hyperglycemia in diabetic
patients improves the potentiation of glucose-stimulated insulin secretion
by GLP-1 and GIP. The aim of this study was to determine whether glycemic
control specifi cally improves the incretin effect in humans. Six type 2 diabetic
subjects with moderate to poor control (age 55±3; BMI 34±2) were studied
twice using a glucose clamp-OGTT protocol before and after 8 weeks of longacting
insulin treatment titrated to a fasting glucose target of 6.0 mM, causing
Hg A1C to reduce from 8.2±0.2 to 6.8±0.2 %. Following an overnight fast and
basal blood draws (-20-0 min), glucose was given intravenously (IV) to raise
blood glucose by ∼6.5 mM. At 90 min 75 g of glucose was given orally, and
the IV glucose infusion was adjusted to maintain the blood glucose constant.
The incretin effect was calculated by comparing plasma insulin levels before
and after the oral glucose load. In the basal period, P1 (0-90 min) and P2 (90-
270 min), the blood glucose levels were 8.6±0.6, 15.1±0.8, and 16.3±1.3 mM
at visit 1; and 5.9±0.6, 13.2±0.8, and 14.3±1.0 mM at visit 2, respectively.
The incremental insulin response to IV glucose (P1) increased from 0.10±0.06
(visit 1) to 0.16±0.08 nM (visit 2). The response to oral glucose ingestion at
fi xed hyperglycemia (P2) increased from 0.42±0.30 (visit 1) to 0.90±0.38 nM
(visit 2). After 8 weeks of treatment, the average increase of the incremental
insulin response to oral glucose was 8 fold greater than the increase to IV
glucose (p=0.2), with 5 out of 6 subjects having a 4 fold or greater increase.
Our data support the hypothesis that intensifi ed insulin treatment to improve
glycemic control leads to a disproportionate improvement of insulin secretion
in response to oral, compared to isoglycemic IV, glucose stimulation in patients
with type 2 diabetes.
Supported by: VA Merit Award to D.D.
For author disclosure information, see page 785.
INTEGRATED PHYSIOLOGY—OTHER CATEGORY HORMONES
A484
1789-P
Involvement of Hypothalamic AMPK and Histamine on Olanzapine-
Induced Glucose Intolerance in Mice
MEGUMI ASATO, YOKO ISHIKAWA, HIROKO IKEDA, ATSUKO KAMEI, KENJI
ONODERA, JUNZO KAMEI, Tokyo, Japan, Kanagawa, Japan
Atypical antipsychotic drugs are well known to produce metabolic
disturbance. Treatment with some atypical antipsychotic drugs such as
clozapine or olanzapine induces the impairment of glucose metabolism,
which increases the risk for developing metabolic side-effects, including
weight gain, dyslipidemia, insulin resistance and hyperglycemia. We have
already reported that central administration of olanzapine produces glucose
intolerance. Recent study showed that clozapine activated adenosine
5’-monophosphate-activated protein kinase (AMPK) through histamine H1
receptors in the hypothalamus. AMPK is known to sense the energy status
of cells and to regulate fuel availability. In central nervous system, AMPK
modulates feeding and systemic energy homeostasis. Thus, it is possible
that atypical antipsychotic drugs such as clozapine and olanzapine induces
glucose intolerance by activating AMPK in the hypothalamus. Therefore, the
present study was designed to investigate the involvement of histamine and
AMPK on olanzapine-induced glucose intolerance. In the glucose CII test,
both intraperitoneally (i.p.) or intracerebroventricually (i.c.v.) administration
of olanzapine dose-dependently induced glucose intolerance as compared
with the vehicle-treated group. The glucose intolerance induced by i.c.v.
treatment with olanzapine was attenuated by i.p. pretreatment with
histamine synthesis inhibitor, α-fl uoromethylhistidine (FMH). The glucose
intolerance induced by i.c.v. treatment with olanzapine was also attenuated
by i.c.v. pretreatment with an AMPK inhibitor, compound C. In addition,
i.c.v. treatment with an AMPK activator, 5-aminoimidazole-4-carboxamide
ribonucleoside (AICAR) also produced the same changes in serum glucose
levels as olanzapine. In the western blot test, olanzapine increased the
phosphorylation of AMPK in the hypothalamus, though total amount of
AMPK was not affected. These results indicate that both histamine and
AMPK in the hypothalamus are involved in the olanzapine-induced glucose
intolerance. Furthermore, the present study suggests that olanzapine might
activate hypothalamic AMPK via histaminergic system.
1790-P
Low Estradiol Concentrations in Males with Hypogonadotrophic
Hypogonadism and Type 2 Diabetes
SANDEEP DHINDSA, RICHARD FURLANETTO, MEHUL VORA, HUSAM GHANIM,
PARESH DANDONA, Buffalo, NY, Chantilly, VA
One-third of men with type 2 diabetes have hypogonadotrophic hypogonadism(HH).
It has been suggested that HH in these men may be due to
an increase in plasma estradiol(E 2 ) concentrations secondary to an increase
in aromatase activity in the adipose tissue which leads to the suppression
of hypothalamo-hypophyseal-gonadal(HHG) axis. We investigated the
hypothesis that plasma E 2 concentrations are signifi cantly greater in type 2
diabetic males with HH as compared to those without HH. Plasma estradiol,
testosterone(T), LH and sex hormone binding globulin(SHBG) concentrations
were measured in fasting blood samples of 236 men with type 2 diabetes
(mean age: 56±12; range:23-83 years; mean BMI: 35±7;range:17-59kg/
m 2 ) attending a tertiary diabetes referral center. Total T was measured by
liquid chromatography tandem mass spectrometry(LC-MS/MS). In 196 men,
total E 2 was measured by an immunoassay. Free E 2 and T concentrations
were calculated using total E 2 , T, albumin and SHBG. In 99 men, total E 2
was measured by the more specifi c LC-MS/MS assay. Free E 2 and free T
concentrations in these men were measured by tracer equilibrium dialysis.
HH was defi ned as free T