Krishna Nagalakshmi.pdf

STUDY OF FIBRINOGEN LEVELS AND ITS
ASSOCIATION WITH GLYCEMIC CONTROL AND
ALBUMIN EXCRETION RATE IN PATIENTS
WITH TYPE 2 DIABETES MELLITUS
By
Dr. NAGALAKSHMI KRISHNA M.B.B.S
A Dissertation submitted to
The Rajiv Gandhi University of Health Sciences
Karnataka, Bangalore
in partial fulfillment of the requirements
for the degree of
DOCTOR OF MEDICINE
IN
GENERAL MEDICINE
Under the guidance of
Dr. MOHAN GOUDAR, M.D.
Professor
DEPARTMENT OF GENERAL MEDICINE
JSS MEDICAL COLLEGE
MYSORE, KARNATAKA
APRIL - 2010

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
KARNATAKA
DECLARATION BY THE CANDIDATE
I hereby declare that this dissertation entitled “STUDY OF FIBRINOGEN
LEVELS AND ITS ASSOCIATION WITH GLYCEMIC CONTROL AND
ALBUMIN EXCRETION RATE IN PATIENTS WITH TYPE 2 DIABETES
MELLITUS” is a bonafide and genuine research work carried out by me under the
guidance of Dr. MOHAN GOUDAR, M.D., Professor, Department of Medicine, JSS
Medical College, Mysore.
ii

CERTIFICATE BY THE GUIDE
This is to certify that the dissertation entitled “STUDY OF FIBRINOGEN
LEVELS AND ITS ASSOCIATION WITH GLYCEMIC CONTROL AND
ALBUMIN EXCRETION RATE IN PATIENTS WITH TYPE 2 DIABETES
MELLITUS” is a bonafide research work done by Dr. NAGALAKSHMI
KRISHNA., under my guidance, in partial fulfillment of the requirements of the MD
DEGREE IN MEDICINE.
iii

ENDORSEMENT BY THE HOD, PRINCIPAL /
HEAD OF THE INSTITUTION
This is to certify that the dissertation entitled “STUDY OF FIBRINOGEN
LEVELS AND ITS ASSOCIATION WITH GLYCEMIC CONTROL AND
ALBUMIN EXCRETION RATE IN PATIENTS WITH TYPE 2 DIABETES
MELLITUS” is a bonafide research work done by Dr. NAGALAKSHMI
KRISHNA., under the guidance of Dr. MOHAN GOUDAR., MD., Professor,
Department of Medicine, JSS Medical College, Mysore.
iv

COPYRIGHT
Declaration by the candidate
I hereby declare that the Rajiv Gandhi University of Health Sciences,
Karnataka shall have the rights to preserve, use and disseminate this dissertation in
print or electronic format for academic / research purpose.
(c) Rajiv Gandhi University of Health Sciences, Karnataka
v

ACKNOWLEDGEMENT
It is with glorious veneration and intense gratitude, I would like to thank my
esteemed teacher Dr. Mohan Goudar M.D., Professor of Medicine, Department of
Medicine, JSS Medical College, Mysore, whose valuable guidance and generous
support facilitated me to accomplish this dissertation.
These few lines can hardly do justice if I try to appraise my gratefulness,
admiration and regards for Dr. K.A. Sudharshana Murthy, M.D., Professor and Head
of the Department of Medicine, JSS Medical College, Mysore, for his exquisite
propositions and expert counsel during my course. I am indebted to him for this
endeavour and look forward for his guidance forever.
I express my sincere thanks to Dr. H. Basavana Gowdappa, Principal and
Ethical Committee Chairman and other members of Ethical Committee, J.S.S.
Medical College for clearing my study.
I am grateful to Dr.H.S.Devaraj, MD, Dr. B.J. Subhash Chandra, MD,
Dr. Ravikumar Y.S MD for their guidance and help in completion of the thesis.
It gives me immense pleasure to express my deep sense of gratitude and
sincere thanks to Dr. Suresh Babu MD, Dr. Kiran MD., Dr. Srinath K.M MD.,
Dr. M. BanuKumar MD., Dr. Narahari S, DNB, Dr. Shasidhara K.C, MD,
Dr. M. Mahesh MD, Dr Adarsh, MD, Dr. Thippeswamy, MD, for their guidance and
encouragement during my postgraduate course.
vi

I express my thanks to all the Staff of Department of Medicine, JSS Medical
College, Assistant Librarian K.P. Basavaraj and Library staff, JSS Medical
College, Mysore, for their kind co-operation.
I am extremely grateful to my father Mr. N. Krishna and my mother
Mrs. Saraswathi for their prayers, support and guidance.
I am extrememly grateful to my friend Sumit and appreciate his contribution
and patience in helping me in preparing this dissertation.
I express my thanks to Mr. Praveen Kumar, Proprietor, M/s. Softouch for
their meticulous work in DTP.
Finally I would like to thank Dr. Prabhakar for sharing his expertise at
statistic and making it seem uncomplicated.
I extend my sincere thanks to my Post-graduate Colleagues, and Friends, who
had helped me in preparing this dissertation.
I thank the almighty in helping me in completing this study.
Last but not the least my heart felt thanks to all patients who formed this
study group and co-operated wholeheartedly.
Place : Mysore Dr. NAGALAKSHMI KRISHNA
Date : Post Graduate Student
Department of Medicine
JSS Medical College, Mysore
vii

LIST OF ABBREVIATIONS
ACE Angiotensin converting enzyme
AGE Advanced glycation end products
AMI Acute myocardial infarction
BMI Body mass index
CAD Coronary artery disease
CHF Congestive heart failure
CRP C-reactive protein
CVD Cardiovascular disease
DKA Diabetic ketoacidosis
DM Diabetes mellitus
ECM Extracellular matrix
ESRD End stage renal disease
FPG Fating plasma glucose
GBM Glomerular basement membrane
GDM Gestational diabetes mellitus
GFR Glomerular filtration rate
HbA1c Glycosylated haemoglobin
HDL High density lipoprotein
ICAM Intercellular adhesion molecule
IFG Impaired fasting plasma glucose
IGT Impaired glucose tolerance
viii

IHD Ischaemic Heart disease
IL Interleukin
IMT Intima media thickness
LDL Low density lipoprotein
MA Microalbuminuria
MCP Monocyte chemoattractant protein
MI Myocardial infarction
NO Nitrous oxide
OCP Oral contraceptive pill
OGTT Oral glucose tolerance test
PAI Plasminogen activator inhibitor
PDGF Platelet derived growth factor
PVD Peripheral vascular disease
STEMI ST elevation myocardial infarction
TCH Total cholesterol
TNF Tumour necrosis factor
UAER Urine albumin excretion rate
VCAM Vascular cell adhesion molecule
VLDL Very low density lipoprotein
ix

Background
ABSTRACT
Globally and nationally, Diabetes Mellitus with its complications has become
the most important contemporary and challenging health problem. The prevalence of
diabetes in India has shown an increasing trend in the last three decades and by 2025,
it is estimated that approximately 79 million Indians will be diabetic.
Persons with type 2 diabetes mellitus are at increased risk for cardiovascular
related illness and death, but this excess risk is not completely explained by an
increased prevalence of the major conventional cardiovascular risk factors such as
smoking, hypertension and hypercholesterolemia. Fibrinogen may have a role in this
excess risk.
Objective
1. To study the fibrinogen levels in patients with Type 2 Diabetes Mellitus.
2. To find the association of fibrinogen with glycemic control and albumin excretion
rate in patients with Type 2 Diabetes Mellitus in addition to assessing risk factors
such as smoking, hypertension, obesity, dyslipidemia
Methods
50 patients who were diagnosed to have Diabetes mellitus based on WHO
criteria and an equal no. of controls(non diabetics) were selected for the study. All
patients in the study were informed about the procedures and consent was taken. The
study design was analytical study. Plasma fibrinogen levels, HbA1c, urinary albumin
x

excretion rate was assessed in addition to assessing risk factors such as smoking,
hypertension, obesity, dyslipidemia.
Results
In this study the mean age was 58.4 years. Fibrinogen levels slightly differed
between men and women. It was observed that in diabetics the mean fibrinogen level
was very high (396.64±164.73) compared to non diabetics (252.6±79.26).
Maximum patients(20) had duration of diabetes more than 5 years with mean
duration of 4.6 years. 54% had poor glycemic control. Microalbuminuria was present
in 50% of cases. 40% of cases were hypertensives, 26% of cases were smokers, with
a mean BMI of 24.6. 38% of cases had non proliferative diabetic retinopathy, 4%
had proliferative diabetic retinopathy. Lipid profiles were significantly abnormal in
the cases (diabetics).
Fibrinogen level was significantly correlated with HbA1c, urine albumin
excretion measured by microalbuminuria.
Fibrinogen level was also significantly correlated with age and other risk
factors like duration of diabetes, elevated total cholesterol, higher triglycerides, and
inversely with HDL . Fibrinogen level was significantly higher in patients with
retinopathy.
Multi-variant logistic regression analysis showed duration of diabetes, total
cholesterol and microalbuminuria to be independent risk factors.
Interpretation and Conclusion
In this study patients with type 2 diabetes mellitus had a high prevalence of
hyperfibrinogenemia. Fibrinogen level was significantly associated with hemoglobin
xi

A1C value and albumin excretion rate measured by microalbuminuria. Clinic based
studies have reported that plasma fibrinogen levels were higher in diabetic patients
than in controls and in diabetic patients with microalbuminuria than in diabetic
patients with normoalbuminuria.
On the basis of the present study findings, it can be concluded that
hyperfibrinogenemia could be a mechanism of the increased cardiovascular risk faced
by patients with type 2 diabetes mellitus.
Keywords : Type 2 diabetes mellitus; fibrinogen; HbA1c; microalbuminuria.
xii

Sl.
No.
TABLE OF CONTENTS
1. INTRODUCTION 1
2. AIMS AND OBJECTIVES 2
3. REVIEW OF LITERATURE 3
4. METHODOLOGY 53
5. RESULTS 58
6. DISCUSSION 78
7. CONCLUSION 85
8. SUMMARY 86
9. BIBLIOGRAPHY 88
10. ANNEXURES
Page
No.
Proforma 106
Master Chart 109
Key to Master Chart 113
xiii

Table
No.
LIST OF TABLES
1 Prevalence of complications of type 2 diabetes in Indians 9
2 Influences on fibrinogen levels 37
3 Age distribution of cases 58
4 Sex wise distribution of cases 59
5 Distribution of diabetics based on duration of diabetes 60
6 Distribution of BMI in diabetics 61
7 Distribution of cases based on optic fundus examination 62
8 Mean lipid levels in cases 63
9 Mean fibrinogen levels in cases and controls 64
10 Distribution of Cases & Controls according to fibrinogen levels 65
11 Association of fibrinogen with age 66
12 Association of fibrinogen with sex 68
13 Association of fibrinogen with duration of diabetes 69
14 Association of fibrinogen with HbA1C 70
15 Association of fibrinogen with microalbuminuria 71
16 Association of fibrinogen with hypertension 72
17 Association of fibrinogen with smoking status 73
18 Association of fibrinogen with BMI 74
19 Association of fibrinogen with retinopathy 75
20 Association of fibrinogen with lipid profile 76
21 Studies comparing levels of fibrinogen with diabetes 79
22 Studies comparing fibrinogen with HbA1C 80
23 Studies comparing fibrinogen with microalbuminuria 81
24 Studies comparing fibrinogen with hypertension 82
25 Studies comparing fibrinogen with smoking status 82
26 Studies comparing fibrinogen with retinopathy 83
27 Studies comparing fibrinogen with lipid profile 84
xiv
Page
Nos.

Chart
No.
LIST OF CHARTS
1 Age distribution of cases 58
2 Sex wise distribution of cases 59
3 Proportion of patients in relation to duration of diabetes 60
4 Distribution of patients in BMI groups 61
5 Distribution of patients with retinopathy findings 62
6 Mean lipid levels in cases 63
7 Mean fibrinogen levels in cases and controls 64
8 Association of fibrinogen with age 67
9 Association of fibrinogen with sex 68
10 Association of fibrinogen with duration of diabetes 69
11 Association of fibrinogen with HbA1C 70
12 Association of fibrinogen with microalbuminuria 71
13 Association of fibrinogen with hypertension 72
14 Association of fibrinogen with smoking status 73
15 Association of fibrinogen with BMI 74
16 Association of fibrinogen with retinopathy 75
17 Association of fibrinogen with lipid profile 76
xv
Page
Nos.

Figure
No.
LIST OF FIGURES
1 Worldwide prevalence of diabetes mellitus 6
2 Global prevalence of diabetes 6
3 Relationship of diabetes-specific complication & glucose tolerance 11
4 Antiatherogenic and proatherogenic effects of insulin 18
5 Screening for microalbuminuria 28
6 Three dimensional structure of fibrinogen 30
7 Fibrinogen and thrombogenesis 41
xvi
Page
Nos.

INTRODUCTION
Diabetes mellitus is a major independent risk factor for cardiovascular disease.
The increase in cardiovascular morbidity and mortality appears to relate to the
synergism of hyperglycemia with other cardiovascular risk factors. 1
Indian studies have documented a prevalence of 21.4% for CAD 2 , 26.9% for
Microalbuminuria and 2.2% for nephropathy among patients with type-2DM. 3
Chronic inflammation precedes the development of Type 2 diabetes which is
now considered an inflammatory condition with insulin resistance. 4,5
Type 2 diabetes is frequently associated with an acute phase reaction
6 ,7
suggestive of low grade inflammatory status.
Risk factors for macrovascular disease in diabetic individuals include
dyslipidemia, hypertension, obesity, reduced physical activity, and cigarette smoking.
Additional risk factors more prevalent in the diabetic population include
microalbuminuria, an elevation of serum creatinine, and abnormal platelet function. 1
Patients with diabetes are also prone to arterial thrombosis due to persistently
activated thrombogenic pathways and impaired fibrinolysis. The presence of high
plasma levels of CRP and fibrinogen are predictive for vascular complications and
cardiovascular death in patients with diabetes. 8
This study was undertaken to evaluate the association of fibrinogen with
glycemic control and albumin excretion rate in patients with type 2 Diabetes mellitus.
1

AIMS AND OBJECTIVES
1. To study the fibrinogen levels in patients with Type 2 Diabetes Mellitus.
2. To find the association of fibrinogen with glycemic control and albumin
excretion rate in patients with Type 2 Diabetes Mellitus in addition to assessing
risk factors such as smoking, hypertension, obesity, dyslipidemia.
2

Diabetes mellitus
REVIEW OF LITERATURE
Diabetes mellitus refers to a group of common metabolic disorders that share
the phenotype of hyperglycemia. Factors contributing to hyperglycemia include
reduced insulin secretion, decreased glucose utilization and increased glucose
production. The metabolic abnormalities associated with DM cause secondary
pathophysiologic changes in multiple organ systems. 1
History
Diabetes (madhumeha / prameha) is probably one of the well described
disorders in Ancient India. The oldest reference to diabetes in Indian literature dates
back to 4,500 years. The charaka samhitha explains about symptoms, complications
and treatment of prameha. The treatment included diet, exercise and medicine. 14,15
Classification
An international expert committee under the sponsorship of American diabetic
association, was established in 1995 and a classification in July 1997.
DM is classified on the basis of pathogenic process that leads to
hyperglycemia as follows: 12
Etiologic Classification of Diabetes Mellitus
I. Type 1 diabetes (beta cell destruction leading to absolute insulin deficiency)
A. Immune-mediated
B. Idiopathic
3

II. Type 2 diabetes (may range from predominantly insulin resistance with relative
insulin deficiency to a predominantly insulin secretory defect with insulin
resistance)
III. Other specific types of diabetes
Genetic defects of cell function characterized by mutations in:
1. Hepatocyte nuclear transcription factor (HNF) 4 (MODY 1)
2. Glucokinase (MODY 2)
3. HNF-1 (MODY 3)
4. Insulin promoter factor-1 (IPF-1; MODY 4)
5. HNF-1 (MODY 5)
6. NeuroD1 (MODY 6)
7. Mitochondrial DNA
8. Subunits of ATP-sensitive potassium channel
9. Proinsulin or insulin conversion
B. Genetic defects in insulin action
1. Type A insulin resistance
2. Leprechaunism
3. Rabson-Mendenhall syndrome
4. Lipodystrophy syndromes
C. Diseases of the exocrine pancreas - pancreatitis, pancreatectomy, neoplasia,
cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, mutations in
carboxyl ester lipase
D. Endocrinopathies - acromegaly, Cushing's syndrome, glucagonoma,
pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma
4

E. Drug or chemical-induced - pentamidine, nicotinic acid, glucocorticoids,
thyroid hormone, diazoxide, thiazides, phenytoin, interferon, protease
inhibitors, clozapine
F. Infections-congenital rubella, cytomegalovirus, coxsackie
G. Uncommon forms of immune-mediated diabetes - "stiff-person" syndrome,
anti-insulin receptor antibodies
H. Other genetic syndromes sometimes associated with diabetes - Down's
syndrome, Klinefelter's syndrome, Turner's syndrome, Wolfram's syndrome,
Friedreich's ataxia, Huntington's chorea, Laurence-Moon-Biedl syndrome,
myotonic dystrophy, porphyria, Prader-Willi syndrome
IV. Gestational diabetes mellitus (GDM)
Note: MODY, maturity onset of diabetes of the young.
Epidemiology of DM-2
The world wide prevalence of diabetes has risen dramatically from 30 million
cases in1985 to 177 million in 2000. 1
by 2030. 13
WHO estimates that > 360 million individuals will have diabetes world wide
5

Fig. 1 : Worldwide prevalence of diabetes mellitus
Fig 2 : Global diabetes prevalence
6

In the United States 18.2 million people are affected by diabetes mellitus, of
which approximately 1 million have type 1 diabetes and the rest mostly have type 2
diabetes. 16
Indian Scenario
According to international diabetes federation, India leads the world in
numbers of diabetics. In 2006, the total no. was 41 million and is projected to rise to
70 million by 2025. 17 The WHO estimates that the number of diabetics in India
would increase to 80 million by 2030. 18
Prior to 1970s several studies have documented the prevalence of Diabetes as
less than 3% even in urban population. 20
However several recent studies, like the National urban diabetes study
(NUDS) in 2001, done in 6 large cities from different regions showed a prevalence of
12.1%, in Hyderabad (16.6%), Chennai (13.5%), Bengaluru (12.4%), Kolkata
(11.7%), New Delhi (11.6%), Mumbai (9.3%). 21
The Amrita Diabetes and endocrine population survey (ADEPS), a community
based cross sectional study done in urban areas of Ernakulam district of Kerala has
revealed a very high prevalence of 19.5% . 22
The Chennai urban rural epidemiology study CURES a recent, large scale
study, done in Chennai using 26,001 individuals, reported an incidence of 15.5%
using WHO criteria, while that of impaired glucose tolerance was 10.6%. The
7

prevalence of type 2 DM had increased from 1989 to 1995 by 39.85% and between
95-2000 by 16.3% and from 2000 to 2004 by 6.0%. Thus within a span of 14 years,
the prevalence of diabetes increased by 72%. 23
Urban – Rural differences in the prevalence of diabetes.
The most disturbing facts in changing trends of diabetes in India, was a shift
of onset to a younger age group including children 26 which was associated with
excess fat and adiposity.
The WHO ICMR national non communicable diseases risk factor
surveillance done in 5 representative states in India, reported a prevalence of 7.3% in
urban, 3.2% in periurban/slums and 3% in rural areas and overall prevalence of 4.3%.
This study done on > 40,000 individuals, showed that the prevalence of diabetes in
urban areas is more than double as in rural araeas 24.
A study done in an urban population in south India using 678 people reported
a prevalence of 21% in people aged above 40 years and the prevalence of diabetes
was significantly higher in subjects whose income was above the mean. 25 The
Chennai urban population study (CUPS) showed a prevalence of 12.4% in middle
income group compared to 6.4% in lower income group. 27
The CURES and CUPS have provided valuable data on the complications of
type 2 diabetes in Indians (Table 1)
8

Table 1 : Prevalence of complications of type 2 diabetes in Indians
Type -2 DM Non diabetics
CAD 21.4% 9.1%
PVD 6.3% 2.7%
The CURES reported an incidence of 17.6% for retinopathy 28. The prevalence
of nephropathy was 2.2% and microalbuminuria26.9%.
It is interesting to note that although the incidence of cardiovascular
complication is higher compared to west, the prevalence of microvascular
2, 29, 30
complication appears to be lower than in Europeans.
The rapid escalation in diabetes prevalence in recent times, may be attributed
to changes in life style that has occurred in post independence India, especially in past
two decades, these include easy availability of calorie rich foods, sedentary life style
and decreased physical activities.
In addition Asian Indians, are also genetically predisposed to type 2 DM, they
have more visceral fat for any given BMI 31 , lower levels of adipokine, adiponectin.
Studies on neonates reported that Indian babies are born smaller but relatively fatter
compared to European babies. 32
Thus apart from lifestyle factors, certain genetic factors also predispose Asian
Indians to type 2 diabetes and related abnormalities.
9

Epidemiologic Determinants and Risk Factors of Type 2 Diabetes
• Genetic factors
• Genetic markers, family history, “thrifty gene(s)”
• Demographic characteristics
• Sex, age, ethnicity
• Behavioral and lifestyle-related risk factors
• Obesity (including distribution of obesity and duration)
• Physical inactivity
• Diet
• Stress
• Westernization, urbanization, modernization
• Metabolic determinants and intermediate risk categories of type 2 diabetes
• Impaired glucose tolerance
• Insulin resistance
• Pregnancy-related determinants (parity, gestational diabetes, diabetes in
offspring of women with diabetes during pregnancy, intrauterine malnutrition
or over nutrition)
Diagnostic criteria for DM-2
The national diabetes data group and WHO have issued diagnostic criteria for
DM, based on :
a) spectrum of FPG and response to OGTT varies among normal individuals.
b) DM is defined as the level of glycemia at which diabetes specific
complications occur.
c) Criteria for diagnosis of DM as advised by the American diabetic association
in 2007 are as follows
10

Criteria for the Diagnosis of Diabetes Mellitus
a
b
c
• Symptoms of diabetes plus random blood glucose concentration 11.1 mmol/L
(200 mg/dL) a or
• Fasting plasma glucose 7.0 mmol/L (126 mg/dL) b or
• Two-hour plasma glucose 11.1 mmol/L (200 mg/dL) during an oral glucose
tolerance test c
Random is defined as without regard to time since the last meal.
Fasting is defined as no caloric intake for at least 8 h.
The test should be performed using a glucose load containing the equivalent of
75 g anhydrous glucose dissolved in water; not recommended for routine
clinical use.
The prevalence of retinopathy in comparison with FPG and 2 hr plasma
34, 35
glucose has been evaluated in two large studies.
There is also association between FPG and 2 hr plasma glucose and macro
vascular and cardiovascular disease. 36 Rates of disease were markedly increased at
FPG> 125 or 2 hr plasma glucose > 140 mg/dl.
The relationship between the blood glucose and risk of retinopathy sharply increase
above the cut off values for diabetes as shown in several studies (figure below).
Fig. 3 : Relationship of diabetes-specific complication and glucose tolerance
11

Screening for type -2 diabetes
It is estimated that up to 50% of 37 affected people remain undiagnosed and
there is a time log of 5-7 yrs between onset of diabetes and diagnosis. 38
The following is the summary of major recommendations for screening for
type – 2 DM. 39
Summary of Major Recommendations for Screening
Recommendations 39
Evaluation for type 2 diabetes should be performed within the health care
setting. Patients should be screened at 3-year intervals beginning at age 45; testing
should be considered at an earlier age or be carried out more frequently if diabetes
risk factors are present.
Diabetes risk factors include:
• A family history of diabetes
• overweight, defined as BMI >25 kg/m 2
• habitual physical inactivity
• belonging to high-risk ethnic or racial group
• previously identified IFG or IGT
• hypertension, dyslipidemia
• history of GDM or delivery of a baby weighing >9 lb and
• polycystic ovary syndrome.
12

Complications of type2 diabetes mellitus 1
Diabetes is characterized by acute and long-term complications: 1
Acute complications
Diabetic ketoacidosis
Non ketotic hyperosmolar state
Hypoglycemia
Chronic complications of diabetes mellitus
Microvasuclar complications
1 Eye disease
• Retinopathy (nonproliferative/ proliferative)
• Macular edema
• Cataracts
2. Neuropathy
• Sensory and motor (mono and polyneuropathy)
• Autonomic
3. Diabetic nephropathy
Macrovascular complications
1. Coronary artery disease
2. Peripheral arterial disease
3. Cerebrovascular disease
13

Others
1. GI-gastro paresis , diarrhea
2. Genitourinary (uropathy /sexual dysfunction )
3. Infections
4. Cataract
5. Glaucoma
6. Periodontal disease
All forms of diabetes, both inherited and acquired, are charecterised by hyper
glycemia, a relative or absolute lack of insulin and the development of diabetes,
specific microvascular pathology in retina, renal glomeruli and peripheral nerve.
Diabetes is now the leading cause of new blindness in people 20 to 74 year of age and
the leading cause of ESRD. 40 Patients with ESRD with DM-2 have life expectancy of
3-4 years.
Diabetes is also associated with accelerated atherosclerotic macrovascular
disease involving heart, brain and lower extremities. The risk of cardiovascular events
is increased 2-6 fold in subjects with diabetes.
Overall, life expectancy is about 7-10 years shorter than for people without
diabetes mellitus because of increased morbidity form diabetic complications 41 .
Pathophysiologic features of microvascular complications:
In the retina, glomerulus and vasavasorum, diabetes-specific macrovascular
disease is characterized by similar pathophysiologic features. 40
1. Requirement of intracellular hyperglycemia
Hyperglycemia is the central initiating factor for all microvascular
complications. Duration and magnitude of hyperglycemia are both strongly correlated
with extent and rate of progression of microvascular disease.
14

In the DCCT, for example type 1 diabetics whose intensive insulin therapy
resulted in HbA1c levels 2% lower than those receiving conventional insulin therapy
had a 76% lower incidence of retinopathy, a 54% lower incidence of nephropathy and
60% reduction in neuropathy. 42
2. Abnormal endothelial cell function
Hyperglycemia causes abnormalities in blood flow and vascular permeability
in retinal, glomerular and vasavasorum, probably by decreasing NO production and
increased sensitivity to angiotensin II. 43
3. Increased vessel wall protein accumulation
The progressive narrowing and eventual occlusion of vascular lumina, may be
attributed to elaboration of growth factors by pericytes and extra cellular matrix
extravasation of growth factors and hypertension induced secretion of pathologic gene
expression.
4. Microvascular cell loss and vessel occlusion
The progressive narrowing and occlusion in vascular lumina are accompanied
by micro vascular cell loss: for example of Muller cells, ganglion cells in retina,
podocyte loss in glomerulus, pericyte degeneration in vasavasorum. 44
5 Development of microvascular complications during post hyperglycemic
Euglycemia – Hyperglycemic memory
This refers to persistent / progression of hyperglycemia induced microvascular
alterations during subsequent periods of normal glucose homeostasis probably
15

secondary to hyperglycemia induced prolonged and sometimes irreversible changes in
long-lived intracellular molecules that persist.
In the DCCT, the effects of former intensive and conventional therapy on the
occurrence and severity of retinopathy and nephropathy were shown to persist for 4
years after the DCCT, despite nearly identical HbA1C values during the 4-year
followup. 45
Genetic determinations of susceptibility to microvascular complication
Different patients with similar duration and degree of hyperglycemia differ
markedly in their susceptibility to microvascular complications. In the DCCT, familial
clustering for retinopathy was seen with odds ratio of 5.4. 49
Various genetic polymorphisms have been implicated. 46
• 5’ insulin gene polymorphism
• 92 m 23+ immunoglobulin allotype
• ACE insertion /deletion polymorphism
• HLA DQB1, O201/302
• Aldose reductase genes.
Pathophysiologic Features of macrovascular complications
Macrovascular disease in diabetics resembles that in subjects without diabetes.
However, subjects with diabetes have more rapidly progressive and extensive
cardiovascular disease, greater incidence of multi vessel disease and a greater number
of diseased vessel segments than non diabetic subjects. 47
16

Although dyslipidemia and hypertension occur with greater frequency in type
-2 diabetes, diabetes itself may confer 75% to 90% of excess risk of CAD in these
patients. 48
Atherosclerosis
induces
Atherosclerosis begins with endothelial dysfunction and injury 50 . This injury
a) Secretion of chemokines such as monocyte chemoattractant protein 1 –MCP1
b) Expression of endothelial adhesion molecules for leucocytes and platelets and
enhance permeability of to lipoproteins and other plasma constituents. This
leads to recruitment of monocyte macrophages to sub endothelial space and
infiltration of plasma LDL, which binds to proteoglycan. LDL undergoes
oxidation and is taken by macrophages.
Activated macrophages and other leucocytes, as well as platelets, stimulates
smooth muscle proliferation and elaboration of ECM leading to lesion filled with
prothrombotic material with a fibrin cap.
Rupture of this fibrin cap, causes thrombus formation, arterial occulsion 51 .
Pathogenesis of endothelial dysfunction in diabetics :
The pathogenesis appears to involve both insulin resistance and
hyperglycemia.
17

Fig. 4 : Insulin has both anti atherogenic and pro atherogenic effects
Anti atherogenic effects of insulin. 52
A. Stimulation of endothelial NO production which inhibits platelet aggregation and
adhesion to the vascular wall.
B. It also decreases expression chemoattractant protein MP 1 and surface adhesion
molecule CD11/CD18 , p-selectin , VCAM-1 and ICAM-1
C. It also reduces vascular permeability and decrease rate of oxidation of LDL
D. Nitrous oxide inhibits proliferation of vascular smooth muscle also.
Two major proatherogenic effects of insulin are
1 Potentiation of PDGF induced smooth muscle proliferation
2 Stimulation of PAI-1 production
Pathway selective insulin resistance internal cells may contribute to diabetic
atherosclerosis.
18

Role of hyperglycemia
Hyperglycemia also inhibits NO production, both in vivo and in vitro. It also
increases PDGF induced smooth muscle cell proliferation and PAI-production 53 . It
also causes increased expression of MCP-1, ICAM-1 and VCAM-1 and increased
secretion of collagen TYPE 4 and fibrinectin.
Both insulin and hyperglycemia also contributes to diabetic dyslipidemia.
Insulin resistance
Insulin resistance is associated with high VLDL, a low HDL and small dense
LDL. Both small dense LDL and low HDL are each independent risk factors for
macrovascular disease. This profile arises as a direct result of increased net free fatty
acid release by insulin resistant adipocytes which stimulates VLDL secretion by
hepatocytes, which depletes HDL and LDL of cholesterol ester. This reduces reverse
cholesterol transport and contributes to formation of small dense LDL.
Hyperglycemia contributes to diabetic dyslipidemia by causing delayed
clearance of post prandial lipoproteins, resulting in elevated levels of atherogenic
cholesterol enriched remnant particles.
The UKPDS identified hyperglycemia as an important risk factor for
macrovascular disease in type-2 diabetes and numerous correlation studies show that
hyperglycemia is a continuous risk factor for macrovascular disease 54
19

Molecular mechanism by which hyperglycemia can induce chronic
complications are 40 :
1. Increased intracellular glucose leads to the formation of AGE’s via non-
enzymatic glycosylation of intra and extra cellular proteins. AGE’s can
accelerate atherosclerosis, promote glomerular dysfunction and alter ECM
function.
2. Increased glucose metabolism via sorbitol pathway which alters redox
potential, increases osmolality, generates free oxygen species.
3. Increased formation of diacyl glycerol leading to activation of protein
kinase- C
4. Increase influx through hexosamine pathway which generates fructose -6
phosphate, a substrate for oxygen linked glycosylation and proteoglycan
production.
Glycemic control and complications 1
The DCCT provided definitive proof that reduction in chronic hyperglycemia
can prevent early complications of Type -1 DM. In this study patients on intensive
diabetic management group achieved a substantial lower hemoglobin A1 C (7.3%)
than those in conventional treatment group (9.1%)
This study demonstrated that improvement of glycemic control reduces NPDR
and PDR (47%) microalbuminuria (39%), clinical nephropathy (54% reduction) and
neuropathy (60% reduction).
There was a non significant reduction in macrovascular events.
20

This study predicted that with intensive management, there was 7.7 additional
years of vision, 5.8 additional years free from ESRD, 5.6 years free from lower
extremity complication. This translated into 15.3 years of life without microvascular
or neurologic complication and 5.1 years of additional life expectancy.
The UKPDS involved 5000 individuals with type 2 DM for > 10 yrs, showed
that each point percentage reduction in HbA1C was associated with 35% reduction in
microvascular complications. Improved glycemic control did not conclusively reduce
CVD mortality but was associated with improvement in lipoprotein risk profiles 55 .
This study also showed that moderate reduction in BP, is associated with reduced risk
of DM – related death, stroke, microvascular complications, retinopathy and heart
failure. 56,57
CAD in type 2 DM
Patients with DM have a greater prevalence of CAD, cardiomyopathy and
congestive heart failure. 58
The Framingham heart study has shown that cardiovascular mortality is twice
in diabetic men and 4 times in diabetic women when compared to non diabetic
patients. 59
The relative risk of AMI is 50% higher in diabetic men and 150% more in
diabetic women.
Also CAD is more extensive (3 vessel) disease and more diffuse in a diabetic
than in a non diabetic. Incidence of left main disease is more common in diabetic
compared to non diabetic.
21

women.
Sudden death occurs 50% more in diabetic men and 300 % more in diabetic
60, 61
Also prevalence of silent MI is more in diabetic.
The role of glycemic control in cardiovascular events is controversial.
Framingham study revealed that reduction in risk of CAD in DM depends
more on prevention and control of associated risk factors such as control of
hypertension, obesity, correction of dyslipidemia, cessation of smoking than glycemic
control. However glycemic control is associated with improvement in lipid profile.
AMI in diabetics commonly presents with atypical symptoms such as
breathlessness, nausea, vomiting and fatigue and absence of chest pain.
The outcomes like mortality are poorer compared to non diabetics. 62
The poorer outcomes may also be related to relative insulin deficiency and
sympathetic overdrive, which might aggravate insulin deficiency. Hence is the need
for strict glycemic control in AMI. 63
DKA is encountered in 4% patients with AMI and carries a poorer prognosis
(85%) mortality. 64
The more common occurrence of MI during early morning hours in non
diabetics is not seen in diabetics, where STEMI can occur evenly throughout the
day. 65 Cardiac autonomic neuropathy in diabetic neuropathy might be related to
severe cardiac arrhythmias and sudden cardiac death in this population.
22

Microvascular complications
1. Diabetic retinopathy
Blindness is 25 times more common in diabetics than non diabetics. Several
Indian studies have also showed a higher incidence of proliferative diabetic
retinopathy, maculopathy and cataract compared to west. 66
Risk factors for diabetic retinopathy.
1. Duration of diabetes
2. Blood glucose control 67,68
3. Hypertension
4. Genetic factor 69,70
Patients with proliferative diabetic retinopathy are at an increased risk for
IHD, diabetic nephropathy and CVA. 71
Renal dysfunction in diabetics
In India diabetic nephropathy is the commonest cause of ESRD.
Diabetic nephropathy is clinically defined by the presence of persistent
proteinuria of >500mg/day in a diabetic patient who has concomitant diabetic
retinopathy and hypertension and in the absence of clinical or laboratory evidence of
other kidney or renal tract disease. 40
The presence of diabetic retinopathy is an important prerequisite because in its
absence, albuminuria in a type 2 diabetic patient may be due to diabetic or non-
diabetic glomeruloscelrosis. 72
Diabetic nephropathy is the leading cause of renal failure worldwide. 73
23

According to Shaw et al migrant Asian Indians had 40 times greater risk of
developing ESRD when compared to Caucasians. 74
Microalbuminuria has been found to be higher in Indian type -2 diabetics
compared to European type – 2 DM (25-41% Vs26-27%) . 75
Microalbuminuria 76
The term microalbuminuria refers to urinary excretion of very small amounts
of albumin 30-300 mg/day or 20-200 μgm/min or albumin creatinine ratio of
30-300μgm/mg or mg/gm or first morning spot sample of urine not detectable by
standard dipstick test for albumin, represents 1 st laboratory evidence of diabetic renal
disease.
The importance of microalbuminuria was first appreciated in early 1980s when
2 groups in London and Denmark independently reported that it was predictive of
later development of overt diabetic nephropathy and progressive renal failure.
AER varies greatly and is affected by Hypertension.
Exercise
Fever
Poor glycemic control
CHF.
Microalbuminuria is secondary to loss of negatively charged proteoglycans
leading to loss of glomerular charge selecting properties and hemodynamic
abnormalities.
24

Microalbuminuria is thought to be a consequence of increased albumin
leakage through the glomerular capillary wall as a result of increased
a. Permeability of the wall or
b. Increased intra glomerular pressure or both.
Hyperglycemia and high BP are accepted risk factors for development of
microalbuminuria. Both increase intra glomerular pressure. In addition hyperglycemia
can alter the charge selectively of the glomerular capillary wall, thereby increasing the
permeability. The presence of microalbuminuria implies dysfunction of the
glomerular filtration barrier. Theoretically, this could result from damage to any of its
layers, including the endothelial glycocalyx.
In healthy kidney > 99% of filtered albumin is reabsorbed in the proximal
tubules. In diabetes, not only is there increased glomerular protein passage but also
there is an absence of compensatory increase in tubular reabsorption of albumin.
Microalbuminuria: marker of endothelial dysfunction 87 and risk factor
for atherosclerosis. 88-93
The glycocalyx that fills the endothelial fenestrae seems to be important for
glomerular size and charge selectively. Abnormalities in endothelial glycocalyx may
contribute to microalbuminuria but also have been implicated in the pathogenesis of
atherosclerosis, thus providing direct link between albuminuria and cardiovascular
disease. 78 A recent animal study did suggest that endothelial glycocalyx loss is
associated with increased permeability to macromolecules in coronary circulation. 77
25

Atherothrombosis is understood as a process in which endothelial dysfunction
and chronic low grade inflammation are important early events; this chronic low
grade inflammation can be assessed by measurement of plasma levels of C-reactive
proteins and cytokines such as IL-6 and TNF–α which is associated with the
occurrence and progression of microalbuminuria and with risk for atherothrombotic
disease. 79,80,81,50
Study done by Sahay et al have shown that microalbuminuria is a marker of
endothelial dysfunction.
• Correlates with systolic hypertension
• Associated with CAD, PVD
• Risk of CAD is higher than ESRD
• Associated with premature atherosclerosis
• Abnormal lipid profile
• Pronounced increased mortality.
A cross sectional study in Western India by Jadav UM, Kadam NN showed
the prevalence of CAD was higher among diabetic subjects with microalbuminuria as
compared to those with normoalbuminuria (58% V/s 31.9%). 82
Varghese A et al in 2001 observed an overall prevalence in microalbuminuria
of 36.3% in patients with type 2 diabetes mellitus in a centre in south India and
observed that microalbuminuric patients had a significantly higher prevalence of
ischemic heart disease compared with normoalbuminuric patients.
26

The relation between urinary albumin excretion rate and vascular disease was
studied in 187 subjects aged over 40 selected from 1084 cases attending diabetic
screening project. CAD was found in 32.2% in subjects with AER of 20mcg /min or
less and in 74% of patients above this. PVD was present in 9.7% of
normoalbuminuric patients and 44% when AER was more than 20mcg /min.
Studies done by Dinneen and Gerstein found that the prevalence of
microalbuminuria in diabetic subjects ranged from 20-36% and was significantly
associated with cardiovascular mortality. Microalbuminuria raised the overall odds
ratio for death to 2.4 and CV mortality to 2 over those without microalbuminuria. 83
Studies of subgroup of diabetic in Framingham heart study also showed
proteinuria to be strong predictor of CAD.
Screening for microalbuminuria 84
Three methods are available for screening for microalbuminuria
1. Albumin creatinine ratio (ACR) performed on the first urine sample of the day.
2. 24 hour urine collection .
3. Timed overnight urine collection.
If assays for microalbuminuria are not readily available, screening with
dipsticks for microalbuminuria may be carried out, since they show acceptable
sensitivity (95%) and specificity (93%) when carried out by trained personal.
27

Management of Microalbuminuria
1) Lowering BP 76
Fig. 5 : Screening for microalbuminuria
This is of paramount importance, the only controversy is: BP targets and
preferred agents. 85 Mogensen suggested that in MA phase retardation of use of AER
would require mean arterial pressure of about 92 mm of mercury (125/75) however;
this has not yet been validated in prospective intervention studies. ACE inhibitors are
preferred over other anti hypertensives.
2) Glycemic control 84
Improved glycemic control reduces development of microalbuminuria in
both types of diabetes. A 10 year study suggested that long term normoglycemia can
reverse even structural renal damage.
28

3) Dietary therapy
Reduction of protein intake. To limit protein intake at the stage of MA to
0.8 - 1g/kg/day and consider replacement of some animal proteins with vegetable
sources.
4) Smoking cessation
Smoking should be discouraged in patients with microalbuminuria to retard
progression of MA and to guard against cardio vascular disease. 76
5) Lipid lowering drugs
The sub study of Prevend intervention Trial 86 supported the usage of statins in
microalbuminuric subjects with the metabolic syndrome to reduce the incidence of
major adverse cardiac events. They used pravastatin 40 mg once a day dosage.
29

FIBRINOGEN STRUCTURE AND PHYSIOLOGY
Fibrinogen is a soluble glycoprotein found in the plasma, with a molecular
weight of 340 KDa. 94 Fibrinogen was the first biological macromolecule visualized by
electron microscopy. 95
The fibrinogen molecule is a dimer consisting of two identical halves, each of
which is composed of three non-identical polypeptides termed A α, B β and γ chains.
The halves of the molecule are connected at the amino-terminal central domain
(N -terminal) by five inter chain disulfide bonds linking the A α chains, the γ chains,
and two pairs between A α 36 and B β 65 that link the A α chain to the B β chain.
The two γ chains are linked in an anti-parallel manner and the three polypeptides of
each half of the fibrinogen molecule are also connected by a series of disulfide
bridges.
Fig. 6 : Schematic representation of Three Dimensional structure of fibrinogen
The A α chain consists of 610, the B β-chain of 461 and the γ-chain of 411
amino acids. Attached to the γ-chains are four carbohydrate side chains, linked
30

through N-acetylglucosamine to asparagine 52 of each gamma-chain and asparagine
364 of each- B βChain: the A α chain does not contain carbohydrates 96 .The molecular
masses of the A α, B β and γ chain including amino acid and carbohydrate
components are 66, 54 and 48 kDa respectively. 96
The overall molecule is an elongated 45nm structure that resolves into a
central dimeric nodule and two peripheral nodules connected with the central nodule
by a thin coiled segment.
It is a trinodular particle with an overall length of 475Å, comprised of two
roughly spherical nodules 65Å in diameter connected by thin threads of 8Å to 15Å in
diameter to a central nodule 50Å in diameter. This structure, visualized by electron
microscopy, is in agreement with results obtained by proteolytic cleavage of
fibrinogen that is, with, plasmin, a process that yields a central dimeric fragment
(Fragment E) and two peripheral monomeric fragments (Fragment D), corresponds to
the central and peripheral nodules visualized by electron microscopy.
MODEL OF HUMAN FIBRINOGEN AND FIBRIN 96
Each half of the molecule is composed of three chains; A α, B β and γ. The
amino terminal regions of the six chains are linked in the central domain (E domain)
by disulfide bonds that form the dimer. In this region, fibrinopeptides A and B are
cleaved from the A α, and B β chains respectively, by thrombin, which converts
fibrinogen into fibrin monomer. The two nodular regions at the C-terminal
(D-Domain) contain complementary binding sites for the central determinants
exposed on release of the fibrinopeptides. Depicted in the figure are also segments of
31

the fibrinogen molecule that bind tissue plasminogen activator (tPA), alpha 2
antiplasmin, factor XIII and of thrombin (11 a) to fibrin. The c-terminal 7-Peptide or
the RGD peptide of the c-terminal of the Aα-chain intervenes in the binding of
fibrinogen with platelets and other cells.
Bio synthesis and metabolism
Gene regulation 95
Human fibrinogen is the product of three closely linked genes, each specifying
the primary structure of A α, Bβ and γ polypeptide chains, located as single copies
within a 50-kilobase region of chromosome 4, bands q 23 to 32. Considerable
homology among, the A α, B β and γ chain indicates that the fibrinogen genes evolved
from a common ancestral gene through a series of duplications and inversions that
began approximately 1 billion years ago.
In normal individuals, the plasma half-life of fibrinogen is 3-5 days and with a
fractional catabolic rate of 25% per day. Plasma fibrinogen is synthesized exclusively
by the hepatocyte, with a steady-state synthetic rate of 1.7 to 5.0 g per day. The
synthetic reserve is large, and upto 20-fold increase in production rates have been
found in patients with peripheral consumption of fibrinogen. 96 Approximately 75% of
the body's fibrinogen is present in the plasma, but it also is distributed in interstitial
fluid and in lymph. Although there is evidence that thrombin and plasmin may play a
role in the normal catabolism of fibrinogen, their overall contribution appears to be
small. The presence of fibrinopeptide A in normal plasma suggests that invivo
coagulation may contribute to catabolism of fibrinogen, which would account for only
32

2-3 % of normal fibrinogen breakdown. Fibrinogen degradation products may have a
specific role in the feedback regulation of fibrinogen synthesis.
An additional fibrinogen pool exists in platelets. Although the megakaryocyte
has been historically considered the site of A alpha, B beta and gamma chain gene
expression and fibrinogen biosynthesis, the origin of megakaryocyte and platelet
fibrinogen is thought to be due to α 1 b and β 3-mediated endocytosis of plasma
fibrinogen and its subsequent storage in α granules. Several extrahepatic sites of
fibrinogen synthesis have been identified, including human cervical, intestinal and
lung carcinoma cells. It has been demonstrated that fibrinogen is assembled into the
extracellular matrix in various cell types. This fibrinogen is conformationally altered
to display the beta15-21 epitope thought to be exposed only to thrombin –generated
fibrin. These data suggest matrix fibrinogen may function in cellular adhesive
interactions or in the maintenance of structural integrity, particularly during
inflammation and wound repair.
Furthermore, Plasma Fibrinogen is also a prominent acute phase reactant 102
The conversion of fibrinogen into an insoluble fibrin can be divided into three distinct
phases:
1. Enzymatic cleavage of fibrinopeptides by thrombin
2. Fibrin polymerization
3. Fibrin stabilization of covalent cross linking by factor Xllla .
Fibrinogen plays a central role in the three major functional processes.
33

coagulation.
The conversion of soluble fibrinogen into insoluble fibrin during blood
The localized assembly and activation of the fibrinolytic system on
polymerized fibrin and binding to blood cells; such as platelets, white cells and
endothelial cells to mediate the inflammatory response, hemostasis, tissue repair and
angiogenesis.
Although primarily recognized for its role in hemostasis, fibrinogen is also
required for competent inflammatory cell reactions in vivo.
Assay for plasma fibrinogen 97
Several accurate methods are now available for the quantitative assay of
plasma fibrinogen, a measurement of great clinical importance that should be
available in all laboratories. Fibrinogen may be converted into fibrin, which is
quantitated by gravimetric, nephelometric or chemical methods. An immunological
method has also been described. Methods involving measurement of coagulable
protein generally are the most reliable and usually serve as the reference standard for
other methods.
Kinetic techniques based on thrombin time, however are simple to perform
and they have been widely adopted.
Both gravimetric methods and those based on the thrombin time underestimate
fibrinogen in the presence of high concentration of fibrin degradation product (FDP);
technical modification designed to avoid these problems have been proposed . 98
34

Sonic nephelometric methods appear to be minimally affected by FDP.
Modified methods that eliminate interference by heparin as well as automated
techniques have been described. Marked difference in fibrinogen level obtained by
gravimetric and immunologic methods and those obtained by functional techniques
are found in patients with inherited dysfibrinogenemias. Reference values to identify
patients with dysfibrinogenemia have been reported.
Thrombin time and related techniques
When thrombin is added to plasma, the time required for clot formation is a
measure of the rate at which fibrin forms. This test (plasma thrombin time) yields
abnormal results when fibrinogen level is below 70-100 mg/dl but is unaffected by the
levels of any of other coagulation factors. It is greatly prolonged by heparin.
The thrombin time may also be prolonged by a qualitatively abnormal
fibrinogen, elevated levels of fibrin-fibrinogen degradation products, certain
paraproteins and hyperfibrinogenemia.
The thrombin time and modification of these are technically simple, can be
performed quickly and are valuable particularly in the diagnosis of DIC.
The reptilase clotting time is similar to the thrombin time in principle, but
coagulation induced by this enzyme which is prepared from snake venom is
unaffected by the presence of heparin.
35

Reference value for test of hemostasis and blood coagulation 99
Test Normal range (±2 SD)
Fibrinogen assay 150-350 mg/dl.
Regional variations in plasma fibrinogen levels
Several epidemiological studies have shown that normal plasma fibrinogen
level ranges from 2.3 to 4.0 g/l, the method of measurement has a strong influence.
Ernst has shown that those studies, which employed the standard method, based on
thrombin coagulation time (Clauss assay) the mean plasma Fibrinogen varied from -
2.1 to 3.1 g/l. This could be attributed to age or sex because only men were selected
for this analysis and patient's ages were similar. This regional variations in the
fibrinogen levels are due to undefined environmental factors and are unrelated to
patients characteristics.
Fibrinogen plays a vital role in number of pathophysiological processes in the
body like: Inflammation, Atherogenesis, Thrombogenesis.
Fibrinogen and inflammation
The process of inflammation is primarily mediated by its interaction with
leukocytes through the surface receptors of the latter termed "integrins". The two
main receptors for fibrinogen on the surface of leukocytes include Mac I and alpha
beta 2. Fibrinogen is also a ligand for intercellular adhesion molecules (ICAM-1) and
enhances monocyte endothelial cell interaction. Fibrinogen upregulates and increases
the concentration of ICAM- I proteins on the endothelial surface, resulting in
increased adhesion of leukocytes to endothelial cells. Moreover the fibrinogen
36

inding to ICAM-1 on endothelial cells also mediates the adhesion of platelets. The
interaction of fibrinogen and cells expressing ICAM-1 is associated with cellular
proliferation. Fibrinogen on binding to its integrin receptor on the surface of
leukocytes also facilitates chemotactic response, thus playing a vital role in
inflammation. Fibrinogen is also involved in the facilitation of both cell-cell
interaction and interaction of cell and extracellular matrix such as collagen.
Table 2 : Possible influences on plasma fibrinogen levels
Factors associated with high fibrinogen Factors associated with low fibrinogen
Black race White colour
Male sex female sex
Advanced age Young age
Smoking Cessation of smoking
Excess weight Weight reduction
Elevated total Cholesterol Regular alcohol consumption
Menopause Regular physical activity
Low economic status Post-menopausal hormone substitution
Physical inactivity Diet rich in n-6 or n-3 PUFA
Oral contraceptive use
Elevated total leucocyte count
Stress
Diet rich in carbohydrates
CLASSIFICATION OF FIBRINOGEN ABNORMALITIES
Fibrinogen abnormalities can be classified as congenital or acquired, with both
groups manifesting quantitative defects (e.g. Afibrinogenemia, hypofibrinogenemia or
hyperfibrinogenemia) or qualitative defects (e.g. Dysfibrinogenemia).
37

Congenital Disorders Of Fibrinogen
1. Afibrinogenemia and Hypofibrinogenemia
2. Congenital dysfibrinogenemia
Acquired abnormalities of fibrinogen
1. Hyperfibrinogenemia
2. Hypofibrinogenemia
3. Dysfibrinogenemia
HYPERFIBRINOGENEMIA
Plasma fibrinogen levels increases significantly with age, with life style habits
such as cigarette smoking and in certain pathologic conditions such as hypertension,
obesity and diabetes mellitus.
20-50% of fibrinogen levels may be genetically controlled, and these
differences may reflect, in part, the ethnic groups that were examined. e.g.: High
fibrinogen in normal individual manifesting with fibrinogen B beta gene
polymorphism at 5'untranslated regions (-455 G/A, - 148 C/T) and BCLI in the
region, fibrinogen as an acute phase reactant protein is sensitive to inflammatory
responses. In this process, the release of interleukin-6 by macrophages leads to
increase in transcription of the B beta gene, resulting in elevated levels of fibrinogen.
The concentration of plasma fibrinogen has clinical implications, as indicated
by several studies demonstrating that hyperfibrinogenemia is an independent risk
factor in stroke and ischemic heart disease. 100
38

Increase in plasma fibrinogen due to genetic polymorphism also seems to be
associated with an increased risk for atherosclerotic cardiovascular diseases. 96
Fibrinogen levels are higher in patients with essential hypertension than in
normotensive controls. Fibrinogen is also elevated in diabetic patients. The
Framingham data revealed a correlation between blood sugar levels and fibrinogen.
Fibrinogen is elevated in patients with type 2 hyperlipoproteinemia and familial
hypercholesterolemia. Fibrinogen and plasma viscosity (strongly determined by
fibrinogen concentration) are associated positively with total cholesterol, triglycerides
and LDL and negatively associated with HDL.
Given these relationships, it is not surprising that fibrinogen was among the
first novel risk factors evaluated. Fibrinogen increases progressively with the extent of
coronary atherosclerosis. Fibrinogen is increased in acute stroke and peripheral
arterial occlusive diseases . 101
Oral contraceptive use results in significant rise of plasma fibrinogen levels,
an effect that seems to be strongest in OCPs with a high estrogen concentration.
However, lower plasma viscosity and plasma fibrinogen are found in women
on hormone replacement therapy (HRT). 94
Genetic influences
Genetic polymorphism account for some 20-51% of variations in fibrinogen
levels, which support the view that fibrinogen, is a primary risk factor for
atherothrombotic disorders rather than just a reflection of such disorder. Beta chain
synthesis is the limiting step in production of mature fibrinogen. 102
39

Van't Hooft et al 103 demonstrated that 455G/A and -854G/A polymorphism of
the beta fibrinogen gene have a significant impact on the plasma fibrinogen
concentration. The 455G/A mutation is the promoter region of the beta fibrinogen
gene is one of the strongest genetic variations, associated with an increase in plasma
fibrinogen in both genders in general population. 104
Fibrinogen strongly affects hemostasis, blood rheology, platelet aggregation
and endothelial function. Fibrinogen is the major determinant of plasma viscosity and
induces reversible red cell aggregation. Both phenomena limit the fluidity of blood.
The hemo rheologic consequences of hyperfibrinogenemia might act at various levels;
by reducing flow, by predisposing to thrombosis, and by enhancing atherogenesis.
105,106 Platelet hyperaggregation plays an accepted role in the genesis of an
atherosclerotic lesion.
Fibrinogen binds to receptors on the platelet membrane, which, in turn is a
precondition for aggregation in vivo.
Furthermore, fibrinogen is also integrated directly into arteriosclerotic
vascular lesions, where it is converted to fibrin and fibrinogen degradation products; it
binds low-density lipoproteins and sequesters more fibrinogen. Both fibrinogen and
fibrinogen degradation products have been shown to stimulate smooth muscle cell
proliferation 107 and migration. These effects suggest that fibrinogen is involved in the
earliest stage of plaque formation. Fibrinogen contributes to cardiovascular disease
by promoting thrombogenesis and atherogenesis.
40

Fig. 7 : Fibrinogen and thrombogenesis
INCREASES
PROMOTES SMC
VISCOSI1TY PROLIFERATION
&
MIGRATION
SUBSTRATE FOR
THROMBINN
COAGULATION
ASCADE
PLATELET
AGGREGATION
Fibrinogen and thrombogenesis
FIBRINOGEN
FIBRIN BINDS TO
LIPOPROTEIN &LDL
&RETAINS THE LIPID
MOIETY IN THE
PLAQUE
ACUTE PHASE
PROTEIN
BINDINGOF
PLASMINOGEN
TO ITS
RECEPTOR
MODULATES
ENDOTHELIAL
FUNCTION
Thrombogenesis is regulated by a fine balance between the coagulation and
fibrinolytic pathways. Subsequent to vessel wall trauma, tissue thromboplastin is
released from the sub-endothelium, which in turn triggers the extrinsic pathway of
41

coagulation by activating factor VII to VIIa. Contact of blood with foreign surface
initiates the intrinsic pathway of coagulation, by activating factor XII to XIIa, as well
as platelets.
The final pathway of the coagulation cascade involves the activation of factors
X to Xa and the subsequent activation of prothrombin to thrombin, which facilitates
the cleavage of fibrinogen into fibrin monomers, which link to each other to form
fibrin polymers and then, to form a stable fibrin clot.
Fibrinogenesis is also involved in final common pathway of platelet
aggregation, by cross-linking the platelets by binding to glycoprotein IIb-IIIa receptor
on the platelet surface. 108
When vascular endothelium is injured, clot formation is instigated by
expression of tissue factor and activation of platelets and the coagulation pathways.
The pivotal reaction is transformation of prothrombin to thrombin with cleavage of
fibrinogen to fibrin.
Fibrinogen and atherogenesis
Fibrinogen and its metabolites appear to cause endothelial damage and
dysfunction. Many human atherosclerotic lesions, showing no evidence of fissure or
ulceration, can contain a large amount of fibrin, which may either be in the form of
mural thrombus on the intact surface of plaque, in layers within the fibrous cap, in
lipid-rich core or diffusely distributed throughout the plaque. This phenomena is
compounded by the decrease in arterial intimal fibrinolytic activity and plasminogen
concentration observed in cardiovascular disease.
42

It has been proposed that once in the arterial intima, fibrin stimulates cell
proliferation by providing a scaffolding along which cells migrate, and by binding
fibronectin, which stimulates cell migration and adhesion. Fibrin degradation
products, which are present in the intima, may stimulate mitogenesis and collagen
synthesis, attract leukocytes, and alter endothelial permeability and vascular tone. In
the advanced plaque, fibrin itself may be involved in the tight binding of LDL and
accumulation of lipid, resulting in the lipid core of atherosclerotic lesions. 94
Atherogenic effects of fibrinogen may result from its interaction with some
lipoproteins. In fact fibrinogen has been shown to modulate the atherogenic effects of
lipoprotein (a) [Lp (a)] and to increase the risk of carotid atherosclerosis and stroke in
patients with low levels of HDL .The association between fibrinogen and carotid
artery disease has been shown to be particularly strong in the elderly. Moreover inter
racial differences have been reported in the levels of fibrinogen, with black persons
having higher levels than white persons and both groups having higher levels than
Asian persons. 109
Hyperfibrinogenemia is associated with a particular histologic composition of
carotid plaques, which in turn may predispose to plaque rupture and thrombosis.
Hyperfibrinogenemia independently of other risk factors, is associated with
macrophage cap infiltration and a decrease in plaque cap thickness, which in turn are
associated with carotid plaque rupture and thrombosis and are probably associated
with the progression of a mature asymptomatic plaque into a symptomatic lesion. 110
43

Fibrinogen appears to enhance atherogenesis directly by its conversion to
fibrin which binds low density lipoprotein and stimulates proliferation of vascular
smooth muscle.
The relationship between inflammatory markers, insulin resistance and
atherogenesis including CAD in type -2 Diabetes mellitus.
Type 2 DM is considered a chronic inflammatory disease, with inflammation
leading to both insulin resistance and contributing to complications of Type 2 DM. 111
In the women’s health initiative study Pradhan AD et al undertook a
prospective nested case – control study, to determine whether elevated levels of IL- 6
and CRP are associated with development of type 2 DM in 27,628 women, over a
period of 4 years. They found that, baseline level of IL-6 and CRP were significantly
higher in those who developed diabetes compared to controls, concluding that higher
levels of CRP and IL -1 predict diabetogenesis. 111
Studies by Temellora and Kurletschiev et al involving German diabetics
found that there is a strong correlation between sub-clinical inflammation markers
fibrinogen, CRP and insulin resistance. 112
In fact a group of polish investigators hypothesized, that metabolic syndrome
be better named as immuno-metabolic syndrome. 113
44

An Indian study done by Deepa R et al in Chennai in the CURES trial, showed
that there is a positive correlation between inflammatory markers (CRD, IL-6,
VCAM-1) with increasing degrees and glucose tolerance among Asian Indians. 114
A Japanese study involving patients with CAD and ACS showed CRP is
markedly elevated in patients with AMI compared to ACS. 115
Studies by Ahmed J et al involving 81 newly diagnosed type-2 diabetics,
where inflammatory markers CRP, Fibrinogen, TNF was estimated and carotid IMT
was measured showed that inflammatory markers are associated with type 2 diabetes
and CRP is correlated with CIMT. 116
A study from Netherlands by Jager A et al showed a strong correlation
between soluble VCAM-1 and cardiovascular mortality in the Hoorn study. 117
A cross sectional data from a subgroup of patients from the Framingham
study, was done by Pon KM et al and showed that the visceral and subcutaneous
adipose tissue volume are cross sectionally related to the markers of inflammation. 118
A Russian study by Doronina concluded that low molecular weight fibrinogen
is strongly correlated with atherogenesis, manifests as CAD, CVA and PVD. 119
Howard SC et al proposed that increasing age and poor glycemic control are
associated with increasing fitrinogen and risk of CAD 120 and stroke. It has been
claimed that inflammatory markers can be monitored cost effectively in patients with
high risk and atherosclerosis. 121
45

The association of fibrinogen with glycemic control and impaired renal function
in Type -2 DM 122
known. 111
The association of markers of inflammation, dyslipidemia and ESRD is well
Dyslipidemia and inflammation may promote renal disease via endothelial
dysfunction in type-2 diabetes.
The population based observational Wisconsin Epidemiologic Study of
Diabetic Retinopathy (WESDR) examined diabetic residents of Wisconsin over time
using measurements of HbA1c and fundoscopy. The study revealed a striking
association between incidence, progression of retinopathy, to macular edema and
vision loss and the level of HbA1c at baseline.
Both the WESDR and a study of type 2 diabetes in an ageing population
(55-75 years old) showed that the relative risk of developing retinopathy increases as
the level of HbA1c increases. Putative risk factors for diabetic retinopathy other than
the level of glycemia, include hypertension, pregnancy, a family history of diabetic
retinopathy, and possibly hypercholesterolemia, but probably not smoking.
A cross sectional study from a subset of patients from Health Professional
Follow up study involving 732 diabetic men, to examine the relation between renal
function and markers of inflammation including CRP, fibrinogen, ICAM and VCAM
and Lipid profile, was done by Julie lin et al in 2006.The GFR was estimated using
MDRD equation. In men with GFR < 60 ml/min, fibrinogen, sTNFR-2 and VCAM,
46

triglycerides were higher when compared to group with GFR > 90 ml/min. Patients
with higher fibrinogen (OR-4.50) had increased odds for GFR < 60. No association
between CRP and GFR was seen.
The authors concluded that several modifiable inflammatory biomarkers are
elevated in setting of moderate renal dysfunction in diabetics and may be the link
between renal insufficiency and increased risk of cardiovascular events in this
population. 123
In the Cardiovascular Health Study Linda Fried et al studied the association
between six inflammatory markers-CRP, fibrinogen, WBC count, factor VII,
hemoglobin levels and albumin with renal function and creatinine in a follow up study
over 7 years. There was a decline in GFR by 3ml/min/year in 58 individuals. Higher
CRP (p

GBM thickening, suggesting a role for inflammation in the pathogenesis of diabetic
nephropathy. 125
The relation between fibrinogen in mild to moderate renal dysfunction was
evaluated in DCCT by Klein RC et al. Elevated levels of fibrinogen have been
associated with progression to overt nephropathy and higher 5- years mortality. 126,127
This study reported that fibrinogen is associated with nephropathy especially in men
but not with retinopathy.
The association of mild to moderate renal dysfunction with inflammatory
markers and the risk of cardiovascular events was studied in the Hoorn study which
concluded that endothelial dysfunction was related to renal function and contributed
to the excess CV mortality in population based cohort with mild renal
insufficiency. 128,129
In Brazil, Gomes MB studied the relationship between acute phase proteins
and microalbuminuria in 64 type 2 diabetics without clinical evidence of
macrovascular disease. They concluded that fibrinogen and acid glycoprotein were
associated with microalbuminuria independent of cardiovascular disease. 130
In an Italian study researchers studied association between inflammatory
marker fibrinogen, hs CRP, VWF and early stages of microvascular complications in
Type I diabetic patients without macrovascular complication. The researchers found a
correlation between low grade inflammation and duration of hyperglycemia. 131
48

Some studies 132 suggest the possibility of association of CRP and VCAM with
elevated AER, but have disputed its role in elevated cardiovascular risk.
Studies have also documented faster rates of decline in glomerular function in
chronic kidney disease and might explain elevated cardiovascular risk. 133
But the role of CRP and leptin have been shown not to be independent risk
factor for non diabetic kidney disease in the MDRD study, underscoring the
importance of inflammation in diabetic nephropathy. 134
In a study involving diabetics and non diabetics undergoing hemodialysis
inflammatory biomarkers along with other factors were associated with higher
mortality in diabetics compared to non diabetics. 135
In addition diabetic patients who smoke have a high chance of progressing to
overt nephropathy compared to those who do not smoke. 136
The relation between urinary albumin excretion rate and vascular disease was
studied in 187 subjects aged over 40 selected from 1084 cases attending diabetic
screening project. CAD was found in 32.2% in subjects with AER of 20μg /min or
less and in 74% of patients above this. PVD was present in 9.7% of
normoalbuminuric patients and 44% when AER was more than 20μg /min.
49

The association of fibrinogen, CRP with UAER in both diabetic and non
diabetic individuals suggests that chronic inflammation may thus be a potential link
between microalbuminuria and macrovascular disease. 137
Studies have shown a strong association between increased UAER, endothelial
dysfunction, and chronic low grade inflammation in type 2 diabetes, to be strongly
correlated with risk of death. 138
In the HOPE (heart outcomes prevention evaluation) study, a cohort study
conducted between 1994 and 1999, individuals aged 55 yrs or more with a history of
CV disease or DM and at least 1 CV risk factor (n=3498) and a base line urine
albumin / creatinine ratio measurement were included. Microalbuminuria was
detected in 1140 of those with DM (32.6%) and 823 (14.8%) of those without DM at
baseline. Microalbuminuria increased the adjusted relative risk of major CV events
(RR, 1.83) 95% confidence interval, (1.64 -2.05), death (RR, 2.09; 95% CI,
1.84-2.38) and hospitalization for congestive heart failure (RR 3.23; 95% C,
2.54-4.10) and concluded that any degree of albuminuria is a risk factor for CV events
in individuals with or without diabetes mellitus. The risk increases with the ACR,
starting well below the microalbuminuria cut off and screening for albuminuria
identifies people at high risk for CV events.
A Japanese study showed a strong association between hs CRP and fibrinogen
with diabetic microangiopathy, but no relation to carotid IMT as a marker of
macroangiopathy. 139
50

Therapeutic implications of inflammation in diabetic microangiopathy and
macroangiopathy
The effect of intensive insulin therapy vs standard treatment was studied in
153 type 2 diabetic patients in Veterans Affairs Cooperative study in type 2 diabetes.
The study found a potentially beneficial reduction in serum triglyceride levels and
preservation of HDL and apoAl level how even it caused a transient elevation in
plasma fibrinogen levels, a possible thrombogenic effect. 140
Markers of endothelial dysfunction and concentration of pro inflammatory
cytokine in type 2 DM are not influenced by improved glycemic control over 16
weeks; but improved metabolic control could be attained with reduced concentration
of CRP, concluded study by Yudkin JS et al. 141
Studies have shown a strong inverse association of HMG coA reductase
inhibitor Atorvastatin and inflammation marker including CRP and fibrinogen both
in acute coronary syndromes and long term therapy with intensive therapy. 142,143
Among antidiabetic agents thaizolidinediones have shown a strong anti-
inflammatory action, with a fall in CRP, fibrinogen ICAM-1 and improvement in
HDL and adiponectin when compared with sulfonylureas. 144,145,146
In obese PCOS women with IGT, Metformin reduced levels of CRP, hyper
insulinemia and cardiovascular risk concluded study by Velija-Asimi Z. 147
51

Treatment with Aspirin, Ticlopidine and other antiplatelet drug is associated
with 10-25% reduction in fibrinogen levels and improvement in vascular
pathology. 148
These studies report that plasma fibrinogen as an inflammatory marker is not
only associated with macrovascular complications, but also with microvascular
disease in type 2 diabetes.
Hence this study was undertaken to evaluate the association of plasma
fibrinogen with glycemic control and urine albumin excretion rate in type 2 diabetes
patients.
52

Source of Data
METHODOLOGY
Patients with type 2 diabetes mellitus admitted to J.S.S. Hospital, Mysore
during the study period from November 2007 to August 2009, fulfilling the inclusion
and exclusion criteria as cases and controls.
Method of collection of data
This was an analytical study. Data for the proposed study was collected in a
pre-tested proforma meeting the objectives of the study. A detailed history and
clinical examination was done pertaining to various risk factors. The patients were
investigated further according to protocol to evaluate the risk factors.
Cases were selected as patients with Diabetes Mellitus who were either
recently detected based on WHO criteria or patients who were on antidiabetic agents
for type 2 diabetes mellitus admitted to the department of medicine in J.S.S.Hospital
during the study period.
Controls were selected from patients admitted to J.S.S.Hospital in
departments of medicine, orthopedics, ophthalmology etc. with no history of DM or
HTN or IHD who were age and sex matched to the cases.
Those patients who gave written consent for the study and fulfilled the
inclusion and exclusion criteria were included.
53

Sample size : (50 cases and 50 controls). The present study involved a total of 100
patients of which 50 were taken as cases(diabetics) and the other 50 as controls(non
diabetics) according to the inclusion and exclusion criteria.
Inclusion criteria
• Cases of Diabetes Mellitus based on WHO criteria.
• Known cases of diabetes mellitus on treatment.
Exclusion criteria
• Type 1 diabetes mellitus.
• Patients with chronic infections, renal disease, endocrine disease, malignancy.
• Patients on warfarin, steroids, hormone replacement therapy.
Following parameters were studied
A. Obesity
Individuals were classified as obese or non obese based on
Body mass index – BMI
BMI = weight (kgs)/height (meters) 2
BMI greater than 30 were considered obese
B. Hypertension
Known hypertensives on treatment or newly detected hypertension according
to JNC VII criteria
C. Ocular fundus examination
54

Ocular fundus was examined by ophthalmologist & diabetic retinopathy was
classified as:
None - normal fundus examination
Non proliferative diabetic retionopathy – NPDR
Proliferative diabetic retinopathy- PDR
D. Diabetes mellitus
A diagnosis of diabetes mellitus was made if patient met the criteria for
diabetes by the ADA 2007 or the patient was already on anti diabetic agents
for management.
E. Dyslipidemia
Fasting blood sample collected for lipid profile, total cholesterol, HDL &
triglycerides were directly assessed by standard enzymatic methods.
LDL cholesterol was estimated using Freidwald’s equation:
LDL cholesterol = Total cholesterol – HDL – triglycerides/5
According to National cholesterol education program (NCEP) ATP III
guidelines patients were considered to have dyslipidemia when
• Total cholesterol >200mg%
• HDL 130mg%
• Triglycerides > 150mg%
55

F. Plasma Fibrinogen level
Plasma fibrinogen was estimated by coagulation method done by Sysmex 560
series.
G. Urine albumin excretion
UAE was measured by microalbuminuria which was detected by Micral test II
strips and was considered positive if there was a colour change. This test is an
immunological, semi quantitative determination of microalbuminuria. In this,
a freshly voided early morning urine sample is collected. The strip is dipped in
urine sample for 5 sec up to in between the two black strips, later withdrawn
and the colour is read after 1 min.
H. Other investigations done
Haemoglobin
Total leukocyte count
Differential leukocyte count
ESR
HbA1c
Blood urea,serum creatinine
Urine analysis
ECG
Chest X-ray
56

STATISTICAL METHODS APPLIED
The analysis of the data was carried out in various parts:
1. In the first part the mean and standard deviation of fibrinogen levels in cases
and controls was estimated.
2. In the second part univariate analysis was carried out to study the differences
in mean level among the factors. The Pearson correlation coefficient was
estimated for each of the variables. The students T test was carried out if two
groups were considered in the variable. For more than 2 groups analysis of
variance (ANOVA) was adopted.
3. In the third part multiple linear regression was adopted to identify the
independent factors from among the factors observed to have significance in
the univariate analysis.
The SPSS software No.13 was utilized for the analysis.
57

A. Age distribution of cases in the study
RESULTS
Table 3 : Frequency of cases in various age groups
Age (Years) Frequency (%)
40-50 13 (26%)
51-60 15 (30%)
61-70 19 (38%)
71-80 3 (6%)
Total 50
Graph 1 : Graph showing number of patients in various age groups
number of patients
The maximum number of cases were in the age group of 61-70 years (38%).
Mean age in the present study was 58.4 years.
58

B. Sex wise distribution of the cases
Table 4 : Sex wise distribution of the cases
Sex Frequency (%)
Male 27 (54%)
Female 23 (46%)
Total 50
Graph 2: Pie chart showing Sex wise distribution of the cases
Males comprised 54% of the study group while females comprised 46%.
59

C. Duration of Diabetes
Table 5 : Frequency of diabetics based on duration of diabetes
Duration Frequency
< 1 year 13 (26%)
1-5 years 17 (34%)
> 5 years 20 (40%)
Graph 3: Pie chart showing proportion of patients in
relation to duration of diabetes
The duration of diabetes in maximum no of cases in this study was more than
5 years with a mean duration of 4.6 years. 4 cases were recently detected and the
longest duration was 15 years.
60

D. Body mass index (BMI)
In the present study, the distribution of BMI in diabetics was as follows
Table 6: No. of patients in BMI groups
BMI Frequency (%)
18-25 30 (60%)
26-30 19 (38%)
>30 1 (2%)
Graph 4 : Graph showing number of patients in BMI groups
number of patients
It was seen that 38% of diabetics were overweight with 1 case being obese.
61

E. Optic fundus finding
In this study, patients were classified based on optic fundus examination
� Normal
� Non proliferative diabetic retinopathy
� Proliferative diabetic retinopathy
Table 7 : Frequency of cases based on optic fundus examination
Fundus Frequency(%)
WNL 29(58%)
NPDR 19(38%)
PDR 2(4%)
Graph 5 : Graph showing No. of pateints with retinopathy findings
number of patients
Fundus
38% of cases had NPDR while 4% of cases had PDR.
62

F. Lipid profile levels
The mean lipid profile among the cases in this study was as follows.
Table 8 : Mean Total cholesterol, LDL, HDL and triglyceride levels
mean lipid levels in mg/dl
Type Mean
Total Cholesterol 208.28 mg/dl
HDL 39.82 mg/dl
LDL 131.80 mg/dl
Triglycerides 183.18 mg/dl
Graph 6 : Graph showing mean lipid levels
63

Analysis Was Carried Out To Study The Fibrinogen Level Among Diabetics and
Non Diabetics and Also Other Factors Associated
1. Mean and standard deviation of fibrinogen levels in diabetics and non
diabetics.
Table 9: Mean and standard deviation of fibrinogen levels in cases (diabetics)
and controls (non diabetics)
Cases
N Mean S.d
(diabetics) 50 396.64 164.73
Controls
(non-diabetics) 50 252.6 79.26
P

(396.64±164.73) compared to non diabetics (252.6± 79.26) which was found to be
very highly significant.
Also, the distribution of diabetics and non diabetics was tabulated by grouping
the fibrinogen levels (Table 10). It was observed that above 500mg/dl of fibrinogen
level, no non diabetics were observed whereas 13 cases (26%) were observed in
diabetics.
Table 10 : Distribution of Cases and Controls according to fibrinogen levels
Fibrinogen (mg/dl) Cases Controls Total
100-200
6
28.60%
15
71.40%
21
100.00%
201-300
11
37.90%
18
62.10%
29
100.00%
301-400
10
38.50%
16
61.50%
26
100.00%
401-500
10
90.90%
1
9.10%
11
100.00%
501-600
7
100.00%
0
0.00%
7
100.00%
601-700
3
100.00%
0
0.00%
3
100.00%
701-800
3
100.00%
0
0.00%
3
100.00%
Total 50 50 100
65

The present study is planned to study the association of fibrinogen with Glycemic
Control and Albumin excretion rate in patients with type 2 diabetes mellitus in
addition to assessing risk factors such as smoking, Hypertension, obesity,
dyslipidemia.
2. Univariate Analysis was carried out to study the differences in mean level
among the factors. The Pearson correlation coefficient was estimated for each
of the variable. The students T test was carried out if 2 groups are considered
in the variable. For more than 2 groups Analysis of variance (ANOVA) was
adopted. The results are as follows.
a) Age and Fibrinogen
Table 11 : Mean and standard deviation of fibrinogen
levels according to age groups
Age groups N Mean Std. Deviation
40-50 13 272.00 121.483
51-60 15 435.20 149.029
61-70 19 446.21 165.655
71-80 3 430.00 191.572
Total 50 396.64 164.730
Pearson’s correlation coefficient =0 .197 (p

Mean fibrinogen levels in mg/dl
Graph 8 : Graph Showing mean fibrinogen levels
in different patient age groups
It was seen that fibrinogen levels showed an increasing trend with age, this was
statistically significant. The Pearson correlation coefficient also showed significance (0.197)
67

) Sex and fibrinogen
Table 12 : Mean and standard deviation of fibrinogen levels according to sex
Sex N Mean Std. Deviation
Male 27 461.33 141.700
Female 23 320.70 159.825
Pearson correlation coefficient = 0.139, p>0.05
sex
Graph 9 : Graph showing mean Fibrinogen levels according to
Mean fibrinogen levels in mg/dl
The mean fibrinogen levels were higher in males when compared to females.
However it was not statistically significant. The Pearson’s coefficient correlation was
0.139 which was also not significant.
68

C. Duration of Diabetes and Fibrinogen
Table 13 : Mean and standard deviation of fibrinogen
level according to duration of diabetes
Duration N Mean Std. Deviation
< 1 year 13 270.62 120.093
1-5 years 17 360.00 128.355
> 5 years 20 509.70 146.549
Pearson correlation coefficient = 0.482, p 5yrs duration had high mean fibrinogen level
(509.70mg/dl) when compared to the duration

D. HbA1c (Glycemic control) and Fibrinogen
Based on HbA1c, 2 groups were obtained i.e. those with adequate glycemic
control (6%), the mean fibrinogen level
in each of these groups was calculated.
Table 14 : Mean and standard deviation of fibrinogen levels
according to HbA1c groups
HBA1C N Mean Std. Deviation
< 6% 23 (46%) 308.22 131.107
> 6% 27(54%) 471.96 154.235
Pearson correlation coefficient = 0.622, p 6% had a higher mean
fibrinogen level (471.96) compared to diabetics with HbA1c

found to be very highly significant. The Pearson correlation coefficient was also very
high (0.622).
E. Urine albumin excretion rate (Microalbuminuria) and fibrinogen
Based on urine albumin excretion rate patients are classified as with
microalbuminuria and without.
Table 15 : Mean and standard deviation of fibrinogen in patients with
microalbuminuria
Microalbuminuria N Mean Std. Deviation
Present 25 520.56 116.292
Absent 25 272.72 99.434
Pearson correlation coefficient = -.647, p

F. Hypertension
In the present study 20 cases (40%) of total 50 cases were hypertensive and
remaining 30 cases were normotensive. The mean fibrinogen levels in hypertensives
and normotensive groups were as follows:
Table 16 : Mean and standard deviation of fibrinogen levels
in hypertensives and normotensives
N Mean Std. Deviation
Hypertensives 20 (40%) 423.50 196.536
Normotensives 30(60%) 378.73 140.408
Pearson correlation coefficient = -.267, p>0.05
Hypertension was observed in 40% of the cases with diabetes. The mean
fibrinogen level between hypertensives and normotensives was observed to be not
significant. The pearson correlation coefficient was -.267 which was also not
significant.
Graph 13 : Graph comparing fibrinogen levels with Hypertension
73

G. Smoking and relation to fibrinogen levels
In the present study 13 out of 50 cases (26%) were smokers and 37 out of 50
cases (74%) were non smokers.
Table 17: The mean fibrinogen levels in smokers and non smokers are as follows
N Mean Std. Deviation
Smokers 13(26%) 398.46 99.150
Non smokers 37 (74%) 396.00 183.458
Pearson correlation coefficient = -.138 p>0.05
No significant difference in mean fibrinogen level was observed between
smokers and non smokers
Graph 14 : Graph showing mean fibrinogen levels in smokers and non smokers
Mean fibrinogen levels in mg/dl
74

H. Body mass index (BMI)
Table 18 : Mean and standard deviation of fibrinogen level according to BMI
BMI Mean Standard deviation
18-25 403 1.955
26-30 396.2 1.792
>30 210 246
Pearson correlation coefficient = .076, p>0.05
Graph 15 : Graph showing mean fibrinogen levels according to BMI
When mean fibrinogen level was compared with respect to BMI, Pearson
correlation coefficient was 0.076, p value was

I. Optic fundus finding
Table 19: Mean fibrinogen levels in patients with diabetic retinopathy
Fundus Examination Mean Fibrinogen
WNL 302.83 mg/dl
NPDR 522.11 mg/dl
PDR 565.00 mg/dl
Pearson correlation coefficient = .689, p

J. Fibrinogen and Lipid profile
Based on lipid profile levels, patients were grouped into two groups.
For Total cholesterol 200mg/dl
LDL Cholesterol 130mg/dl
HDL Cholesterol >40 and 40

It was observed that in lipid profiles total cholesterol, HDL and Triglycerides
had significant difference in the 2 groups presented in table 20.
3. The multiple linear regression was adopted to identify the independent
factors from among the factors observed to have significance in the
univariate analysis. The independent factors were duration of diabetes, total
cholesterol and microalbuminuria.
The SPSS software No.13 was utilized for the analysis.
78

DISCUSSION
Fifty patients with Type 2 Diabetes Mellitus and 50 controls (non diabetics)
were studied. It was found that patients with Type 2 Diabetes Mellitus had an elevated
prevalence of hyperfibrinogenemia and that in diabetics plasma fibrinogen level was
associated with HbA1C and albumin excretion rate. Higher fibrinogen levels were
observed in diabetics with longer duration, patients with increasing age, poor
glycemic control, dyslipedimia, presence of retinopathy and microalbuminuria.
As discussed previously fibrinogen as a prothrombotic marker can be affected
by various markers.
In this study significantly higher fibrinogen levels were found in patients with
• Those with longer duration of diabetes (p

A) Association of fibrinogen with diabetes
Several studies have shown significantly higher levels of fibrinogen in
diabetics compared to non diabetic population. 122,149,152
Table 21: Studies comparing levels of fibrinogen with diabetes
Study Mean fibrinogen levels(mg/dl)
Bruno G et al 122
Lee AJ et al The Scottish Heart Study 149
360
Diabetic Men =246
Women=244
Mistry P et al 152 Cases =521.5
Controls=478.9
P

In the present study it was found that the mean fibrinogen levels were higher in
males(461.33 mg/dl) when compared to females(320.70mg/dl), however it was not
statistically significant.
D) Association of fibrinogen with HbA1c (glycemic control)
Hyperfibrinogenemia in diabetes has been reported to be caused by an
increased synthesis of fibrinogen that is not compensated for by a proportional
increase in clearance of fibrinogen. These abnormalities have been associated with
insulin deficiency and have been corrected with insulin, 153 suggesting that
hyperfibrinogenemia is an expression of poor glycemic control. It has been reported 154
that fibrinopeptide A (a peptide that is released from fibrinogen when it is
transformed into fibrin) is positively related to blood glucose. In a study done by
Bruno G et al 122 fibrinogen level was significantly associated with hemoglobin A1c
value. Another study by Ceriello A 155 suggested that hyperfibrinogenemia is one way
by which hyperglycemia activates coagulation. Therefore, both epidemiologic and
clinical findings support the hypothesis that poor glycemic control may lead to
thrombophilia, a condition that might be involved in the increased cardiovascular risk
in patients with diabetes.
Table 22 : Studies comparing fibrinogen with HbA1C
Study Relation between fibrinogen in patient with glycemic
control (HbA1C)
Bruno G et al 122
Adequate glycemic control group = 344 mg/dl
Patients with poor glycemic control = 380 mg/dl :
p

In the present study it was observed that the mean fibrinogen level was higher
in patients with poor glycemic control which is in tune with the study done by Bruno
G et al 122
E. Microalbuminuria and fibrinogen levels
Fibrinogen levels were significantly higher in patients who had
microalbuminuria compared to those with no proteinuria (p

E) Association of fibrinogen with hypertension
Higher levels of fibrinogen were seen in patients with hypertensive patients
compared to normotensives in studies by Lee AJ et al 149 and Mistry P et al. 152
Table 24 : Studies comparing Hypertension and fibrinogen levels
Lee AJ et al The Scottish
Heart Study
Author Mean fibrinogen in
hypertensives
Men=239
Women=238
Mistry P et al Cases =554
Present study 423.5±196.5
Mean fibrinogen in
normotensives
Men =227
Women=231
Controls =443
378.7±140.4
In the present study higher levels of fibrinogen were seen in hypertensive
patients compared to normotensives, however it was not statistically significant
(p value > 0.05)
F) Smoking status and relation to fibrinogen levels
No relation was seen between fibrinogen levels and smoking status. This is in
contrast to several studies which report higher fibrinogen levels in smokers.
Table 25 : Studies comparing fibrinogen levels in smokers and non smokers
Study Mean fibrinogen
in smokers
Mean fibrinogen
in non smokers
P value
Mistry P et al 515.8±77 443.4±99 0.05–not
significant
A meta analysis by Ernst et al 150 showed a significantly higher levels in
smokers compared to non smokers.
82

The non association between smoking status and fibrinogen levels in the
present study might be due to the fact that the number of smokers in the present study
was small (n=13)
H) Fibrinogen and retinopathy
Fibrinogen levels were significantly higher in patients with diabetic
retinopathy. Patients with non proliferative diabetic retinopathy had significantly
higher levels of fibrinogen compared to those with normal optic fundus (p

Study
Gothenger risk,
incidence and
prevalence study
Caerphilly &
Speedwell
collaborative
heart study
Table 27: Studies comparing Lipid profile and fibrinogen levels
Relation of
fibrinogen to
total
cholesterol
R=0.124
P

� This is a hospital based small study of a short duration.
85

CONCLUSION
In this study patients with type 2 diabetes mellitus had a high prevalence of
hyperfibrinogenemia. Higher fibrinogen levels was associated with increasing age,
longer duration of diabetes, dyslipidemia and presence of retinopathy.
Fibrinogen level was significantly associated with hemoglobin A1C value and
albumin excretion rate measured by microalbuminuria. Clinic based studies have
reported that plasma fibrinogen levels were higher in diabetic patients with
microalbuminuria than in diabetic patients with normoalbuminuria. Because
microalbuminuria has been recognized as a powerful predictor of cardiovascular
related illness and death, fibrinogen level may be considered a potential additional
risk factor in patients with diabetes which suggests that fibrinogen may be involved in
the increased cardiovascular risk of patients with diabetes mellitus.
On the basis of the present study findings, it can be concluded that
hyperfibrinogenemia could be a mechanism of the increased cardiovascular risk faced
by patients with type 2 diabetes mellitus.
85

SUMMARY
• In this study 50 patients with type 2 diabetes were studied and compared with 50
age and sex matched controls in relation to fibrinogen levels. The association of
fibrinogen with glycemic control and albumin excretion rate in patients with Type
2 Diabetes Mellitus in addition to assessing risk factors such as smoking,
hypertension, obesity, dyslipidemia was also studied.
• The maximum number of cases were in the age group of 61-70 years(38%), with
mean age of 58.4 years.
• Males comprised 54% of the study while females comprised 46%.
• It was obsereved that in diabetics the mean fibrinogen level was very high
(396.64±164.73) compared to non diabetics (252.6±79.26) which was found to be
very highly significant (p value

was131.80 mg/dl, mean HDL 39.82mg/dl, and mean triglyceride was
183.18mg/dl.
• Fibrinogen level was significantly correlated with HbA1c (p

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106

PROFORMA
STUDY OF FIBRINOGEN LEVELS AND ITS ASSOCIATION
WITH GLYCEMIC CONTROL AND ALBUMIN EXCRETION
RATE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS
1.GENERAL INFORMATION :
a. Name
b. Age
c. Gender
d. Occupation
e. Inpatient number
f. Date of admission
2. CHIEF COMPLAINTS:
3. PAST HISTORY:
Diabetes mellitus Yes/No Duration- On treatment- Yes/No
Hypertension Yes/No Duration- On treatment- Yes/No
Dyslipidemia Yes/No Duration- On treatment- Yes/No
Ischemic heart disease Yes/No Duration- On treatment- Yes/No
Cerebrovascular accident Yes/No
Thyroid disorder Yes/No
Liver disease Yes/No
Renal disease Yes/No
4. FAMILY HISTORY:
Diabetes mellitus Yes/No
Hypertension Yes/No
Dyslipidemia Yes/No
Ischemic heart disease Yes/No
106

5. DRUG HISTORY :
NSAID’s Yes/No
Steroids Yes/No
Oral anticoagulants Yes/No
Hormone replacement therapy Yes/No
6. PERSONAL HISTORY:
Smoking Yes/No
Alcoholism Yes/No
Diet Veg/Non veg
7 . General Physical Examination:
Height : ______ cms BMI : _____ kg/m 2
Weight : ______ kgs
Pulse : ____ /min
Blood Pressure : _____ mm Hg
Peripheral pulses : felt/not felt
8. Systemic Examination :
Respiratory system :
Cardiovascular system :
Abdominal system :
Central nervous system :
9. Investigations :
Hb: ____ gm%
TC : ____ cells/cumm
DC : N __ L __ M __ E __
107

ESR: ____ at 1 hr
RBS : ____ mg/dl
FBS : ____ mg/dl
PPBS : ____ mg/dl
HbA1C : ___ %
Blood urea : ____ mg/dl
Serum creatinine: ____ mg/dl
Urine routine :
Fasting lipid profile : Total cholesterol : ___ mg/dl
HDL : ___ mg/dl
LDL : ___mg/dl
VLDL : ___ mg/dl
TG : ___mg/dl
Plasma Fibrinogen : ____ mg/dl
Microalbuminuria : Present/Absent
Fundus examination : Normal / NPDR / PDR
ECG :
Chest X-ray :
108

Sl.
No
Name AGE Sex DM-
Dur
Anti-
DM
MASTER CHART
CASES
HTN SM BP BMI Fundus Hb% TC ESR RBS HbA1c Blood
urea
Serum
creatinine
FIB TCH HDL LDL TG MA
1 BASAVA 56 M 7 1 1 2 140/90 23 WNL 13.2 8900 15 283 8.0 36 1.3 646 230 40 142 240 1
2 GOWRAMMA 45 F 1 1 1 2 160/90 24 WNL 13.1 5400 50 245 5.4 22 0.9 165 187 52 105 148 2
3 AKKAYAMMA 60 F 5 1 1 2 130/80 23 NPDR 12.1 7800 20 270 8.5 38 1.4 650 224 37 109 389 1
4 SIDDEGOWDA 63 M 10 1 2 2 120/80 24 NPDR 14 7900 30 312 10.4 34 1.3 760 280 32 206 212 1
5 SIDDARAO 70 M 12 1 2 2 120/80 21 WNL 13.2 6100 25 180 5.2 24 1.0 180 150 40 74 180 2
6 RANGANATH 65 M 8 1 2 2 130/80 22 WNL 13.1 7200 40 248 8.4 28 1.2 350 212 35 137 200 1
7 MARIYAPPA 65 M 6 1 2 1 140/90 26 WNL 14 9600 30 221 5.2 25 0.9 330 213 38 146 143 2
8 EREGOWDA 51 M 3 1 1 1 160/80 26 NPDR 14 7400 45 243 7.5 32 1.1 380 240 41 163 180 1
9 NEELAMMA 45 F ND 2 2 2 140/90 24 WNL 14 9200 40 300 5.2 36 0.8 270 240 32 178 150 2
10 JAYALAKSHMI 58 F 1 1 1 2 160/90 24 WNL 12 8400 40 367 5.6 18 0.8 152 130 40 60 150 2
11 BASAPPA 70 M 5 1 2 1 120/80 27 NPDR 10.2 17700 76 280 8.4 28 0.7 370 220 25 149 230 1
12 ESHWAR 52 M 1 1 2 1 136/90 26 WNL 14 8900 50 486 9.6 20 0.8 460 194 47 78 345 2
13 NAGARAJU 53 M 3 1 1 2 170/100 24 NPDR 12 4400 10 422 8.4 45 1.5 460 233 51 115 334 1
14 VENKATA 49 M 2 1 2 1 130/80 22 WNL 13 7100 30 152 8.0 40 1.3 490 150 30 90 150 1
15 SUMA 45 F 1 1 2 2 130/80 25 WNL 13 8000 20 250 5.2 26 0.6 260 238 27 168 214 2
16 SRINIVAS 62 M 1 1 2 1 130/80 23 WNL 14 5600 10 178 5.0 27 0.8 320 202 46 128 140 2
17 PARVATHAMMA 68 F 10 1 1 2 150/90 26 NPDR 10.2 8900 40 214 6.8 38 1.2 460 169 48 65 278 1
18 NARAYAN 68 M 5 1 2 2 130/80 26 NPDR 8.7 7000 10 246 5.8 42 1.3 510 200 32 136 160 1
19 PUTTASOMAPPA 63 M 15 1 1 2 170/100 25 NPDR 12 6900 30 205 7.2 38 1.4 750 250 35 173 210 1
20 LINGEGOWDA 67 M 10 1 2 1 160/90 26 NPDR 11 6500 35 238 8.0 36 1.3 570 240 40 164 180 1
21 GIRIJAMMA 48 F 1 1 2 2 120/80 24 WNL 11.2 8000 60 424 5.8 27 1.0 190 168 23 127 90 2
22 MALLEGOWDA 63 M 3 1 2 1 120/80 26 WNL 14 10600 40 183 5.2 33 0.6 310 130 40 58 160 2
23 NINGAMMA 50 F 0.25 1 2 2 130/80 24 NPDR 13.5 7900 20 291 5.6 28 0.8 572 242 30 170 210 2
24 KALAMMA 50 F ND 2 2 2 120/80 26 WNL 10.8 8400 10 497 6.2 16 1.0 250 190 45 118 135 2
25 NANJAMMA 68 F 9 1 1 2 150/90 26 NPDR 9 4200 30 315 7.2 41 1.3 718 240 38 170 160 1
109

26 JAYAMMA 50 F ND 2 1 2 140/80 23 WNL 10.6 7600 20 263 7.4 22 1.1 195 260 42 186 162 2
27 PADMA 65 F 3 1 2 2 130/70 23 WNL 12 7800 40 225 5.2 34 0.8 370 190 42 126 110 2
28 PUTTARAJEGOWDA 72 M 7 1 1 2 150/90 23 NPDR 12 10100 30 320 9.0 40 1.2 560 198 39 120 197 1
29 PARVATHAMMA 53 F 2 1 2 2 130/80 31 WNL 11 6000 20 245 5.8 31 0.9 210 220 38 160 110 2
30 KANTHAMMA 50 F 0.5 1 2 2 120/80 27 WNL 12 6000 10 210 5.4 18 0.7 240 249 40 188 105 2
31 BEEREGOWDA 55 M 6 1 1 2 160/80 25 WNL 13 8600 30 268 5.8 34 1.1 580 230 38 158 170 1
32 SAVITHRAMMA 50 F 1 1 1 2 170/80 23 WNL 12 8000 20 230 6.4 24 1.3 210 185 40 124 105 2
33 MAHADEVAPPA 60 M 5 1 2 1 130/80 27 NPDR 12 6300 20 210 8.4 32 1.5 470 182 49 94 195 1
34 MARISWAMY 68 M 3 1 2 1 130/80 26 WNL 10 8100 10 206 5.4 29 0.9 210 268 42 197 145 2
35 MADEGOWDA 52 M 7 1 1 2 140/80 21 PDR 12 8000 20 172 7.4 46 1.5 610 221 48 146 136 1
36 SANNAIAH 68 M 3 1 1 1 160/80 26 WNL 11 11600 20 267 5.4 22 1.0 370 196 40 126 148 2
37 VENKATESH 62 M 7 1 1 2 130/80 23 NPDR 13 5600 20 321 7.6 38 1.1 430 251 40 174 184 1
38 BASAVARAJ 51 M 3 1 2 1 120/80 25 WNL 14 13000 30 186 5.4 21 0.7 380 220 45 147 140 2
39 SINGEGOWDA 75 M 10 1 2 1 170/80 28 PDR 10 7300 20 261 7.6 35 1.6 520 162 42 78 210 1
40 JAMIARA JAN 45 F ND 2 1 2 140/80 26 WNL 10 9100 10 210 10.4 26 0.8 234 188 42 110 180 2
41 SIDDEGOWDA 62 M 8 1 2 2 130/80 27 NPDR 15 9000 45 210 8.0 41 1.4 470 195 45 83 335 1
42 GOVINDEGOWDA 56 M 6 1 1 2 160/80 23 NPDR 15 7800 20 290 8.0 44 1.3 440 178 42 114 109 1
43 MAHADEV 65 M 10 1 2 2 120/80 24 NPDR 11 9000 30 320 5.4 36 1.0 530 222 48 138 182 1
44 VIDYA 44 F 2 1 1 2 150/80 23 WNL 12.7 6800 10 190 5.6 22 1.1 180 206 32 126 241 2
45 KAMALAMMA 60 F 7 1 2 2 130/90 22 WNL 10.9 9000 20 320 8.2 32 1.1 470 212 46 126 200 1
46 PARVATHAMMA 70 F 7 1 2 2 120/80 24 NPDR 10 8300 30 213 6.8 36 0.9 430 197 46 121 151 1
47 GOWRAMMA 55 F 3 1 2 2 130/80 26 WNL 13 8500 30 17 5.0 25 1.0 270 176 48 98 148 2
48 SHARADAMMA 60 F 6 1 2 2 140/90 27 NPDR 10 9500 20 240 7.4 38 1.3 390 207 40 117 248 1
49 JANAKI 75 F 4 1 2 2 120/80 23 WNL 14 9300 20 210 5.2 36 0.9 210 212 34 153 127 2
50 VANAJAMMA 45 F 2 1 1 2 150/90 22 WNL 14 10000 20 230 5.8 27 0.6 280 217 39 151 133 2
110

Sl.
No
Name AGE Sex DM-
Dur
Anti-
DM
CONTROLS
HTN SM BP BMI Fundus Hb% TC ESR RBS HbA1c Blood
urea
Serum
creatinine
FIB TCH HDL LDL TG MA
1 SOMASHEKHAR 56 M 0 2 2 2 130/90 23 WNL 12.2 4900 25 96 4.0 22 0.8 216 122 38 48 178 2
2 GURUMALLAMMA 45 F 0 2 2 2 120/80 24 WNL 11.1 5400 40 98 4.2 34 1.0 324 154 40 85 145 2
3 MAHADEVAMMA 60 F 0 2 2 2 130/80 23 WNL 12.1 7600 25 102 5.0 23 1.2 224 112 42 33 185 2
4 BORAIAH 63 M 0 2 2 2 120/80 24 WNL 14 5900 35 124 3.8 25 1.0 187 167 44 98 125 2
5 NANJAPPA 70 M 0 2 2 2 120/90 21 WNL 13.6 7100 25 132 4.4 18 0.8 375 183 45 103 174 2
6 GOVINDEGOWDA 65 M 0 2 2 2 130/80 22 WNL 13.4 7100 40 108 4.6 32 0.7 124 157 42 78 184 2
7 RAMANAIKA 65 M 0 2 2 2 140/90 25 WNL 14 6600 30 78 5.0 28 0.6 324 143 43 65 175 2
8 NARASIMHA 51 M 0 2 2 2 130/80 26 WNL 14 5400 35 112 4.0 23 1.0 128 187 38 129 102 2
9 SUNDRAMMA 45 F 0 2 2 2 140/90 24 WNL 14 4200 40 135 4.2 22 1.1 248 201 46 135 98 2
10 LAKSHMAMMA 58 F 0 2 2 2 120/90 24 WNL 11 6400 30 96 4.6 18 1.2 234 122 40 57 125 2
11 VENKATEGOWDA 70 M 0 2 2 1 120/80 23 WNL 12 7700 35 125 3.8 34 1.2 420 210 45 139 132 2
12 RAMACHANDRA 52 M 0 2 2 2 136/90 26 WNL 14 8100 50 135 4.6 32 0.8 145 154 47 70 184 2
13 KUMARASWAMY 53 M 0 2 2 2 120/80 24 WNL 12 4400 10 95 4.2 30 0.9 165 176 48 105 115 2
14 SWAMIGOWDA 49 M 0 2 2 2 130/80 22 WNL 12 7100 30 106 3.8 20 1.1 258 182 42 104 182 2
15 NANJAMMA 45 F 0 2 2 2 130/80 25 WNL 11 5000 10 128 4.2 21 1.0 326 195 40 126 145 2
16 EREGOWDA 62 M 0 2 2 1 130/80 23 WNL 14 5600 10 88 4.6 25 0.7 112 122 47 36 195 2
17 SUBBAMMA 68 F 0 2 2 2 140/90 22 WNL 10 6200 40 114 4.4 36 0.9 245 154 42 88 120 2
18 MARAIAH 68 M 0 2 2 1 130/80 23 WNL 13 7000 20 121 4.4 32 0.7 312 176 50 103 116 2
19 SUBBAIAH 63 M 0 2 2 2 150/90 25 WNL 12 6000 30 105 4.2 26 0.9 148 138 48 71 97 2
20 MALLAPPA 67 M 0 2 2 2 140/90 26 WNL 13 6500 35 79 4.6 28 1.1 188 136 46 65 125 2
21 SUKANYA 48 F 0 2 2 2 120/80 24 WNL 11 8000 40 104 4.8 21 1.2 286 187 43 112 161 2
22 MADAPPA 63 M 0 2 2 2 120/80 26 WNL 14 5600 40 123 4.2 18 0.9 380 126 42 58 130 2
23 LAKSHMAMMA 50 F 0 2 2 2 130/80 24 WNL 13.5 5900 20 132 3.8 25 1.0 254 152 48 73 153 2
24 SHANTHA 50 F 0 2 2 2 120/80 26 WNL 10.8 6400 10 108 4.6 20 1.2 264 169 43 98 140 2
25 GOWRAMMA 68 F 0 2 2 2 130/80 26 WNL 10 4200 30 76 4.2 24 0.6 318 173 44 93 180 2
111

26 SUVARNAMMA 50 F 0 2 2 2 140/80 23 WNL 10.6 6600 20 98 4.4 30 0.8 284 146 45 73 138 2
27 CHIKKAMMA 65 F 0 2 2 2 120/70 23 WNL 12 7200 40 102 4.8 40 1.3 168 184 48 103 163 2
28 JAVARAPPA 72 M 0 2 2 1 140/90 23 WNL 12 8100 30 124 4.2 32 1.0 390 204 40 134 150 2
29 RAJAMMA 53 F 0 2 2 2 130/80 23 WNL 11 6000 20 131 4.6 22 1.1 224 168 42 88 188 2
30 KEMPAMMA 50 F 0 2 2 2 120/80 27 WNL 12 6000 10 105 4.4 26 1.0 340 152 48 79 125 2
31 MADEGOWDA 55 M 0 2 2 2 130/80 25 WNL 13 5600 30 121 4.4 34 0.9 264 169 46 86 186 2
32 PREMA 50 F 0 2 2 2 140/80 23 WNL 12 6000 20 106 3.8 20 0.6 196 135 47 56 160 2
33 SAMPIGAIAH 60 M 0 2 2 2 130/80 21 WNL 12 6300 20 99 4.6 18 0.9 226 179 49 92 192 2
34 MANJEGOWDA 68 M 0 2 2 2 120/80 26 WNL 10 8100 10 112 4.4 22 1.2 134 163 48 82 165 2
35 MAHADEVAPPA 52 M 0 2 2 2 140/80 21 WNL 12 8000 20 125 4.2 20 0.8 324 157 44 73 198 2
36 KRISHNEGOWDA 68 M 0 2 2 1 120/80 26 WNL 11 7600 20 132 4.6 32 0.7 220 186 42 119 125 2
37 SANNAPPA 62 M 0 2 2 2 130/80 23 WNL 13 5600 40 124 4.8 30 1.1 360 138 48 67 115 2
38 RAMAKRISHNA 51 M 0 2 2 2 120/80 25 WNL 14 5000 30 97 4.0 20 1.3 194 154 44 89 107 2
39 PUTTASWAMY 75 M 0 2 2 2 140/80 23 WNL 10 6300 20 96 4.2 24 0.9 245 134 42 68 120 2
40 CHIKKATHAYAMMA 45 F 0 2 2 2 140/80 26 WNL 10 6100 10 112 4.2 30 0.7 318 154 40 77 185 2
41 RAJEGOWDA 62 M 0 2 2 1 130/80 24 WNL 14 7000 45 133 3.8 25 1.2 326 178 42 116 99 2
42 MADAIAH 56 M 0 2 2 2 130/80 23 WNL 14 6800 20 86 4.2 18 0.7 128 198 48 133 85 2
43 VEERAPPA 65 M 0 2 2 2 140/90 24 WNL 11 7000 30 128 4.6 36 1.1 188 154 46 77 156 2
44 DEVAMMA 44 F 0 2 2 2 140/80 23 WNL 12.2 5800 10 88 4.8 26 1.0 248 126 48 61 85 2
45 CHIKKATHAYAMMA 60 F 0 2 2 2 130/90 22 WNL 11 4000 20 125 4.2 21 0.8 192 163 42 97 120 2
46 MALLAMMA 70 F 0 2 2 2 120/80 24 WNL 10 8300 30 115 4.6 20 0.6 365 178 48 97 165 2
47 ANNAMARY 55 F 0 2 2 2 130/80 26 WNL 13 8500 30 100 4.8 28 1.1 224 192 42 122 141 2
48 JAVANAMMA 60 F 0 2 2 2 140/90 26 WNL 10 5500 20 96 5.0 26 1.0 315 162 40 98 120 2
49 KALAMMA 75 F 0 2 2 2 140/80 23 WNL 14 6300 20 102 4.4 22 0.9 228 167 42 87 188 2
50 MAHADEVAMMA 45 F 0 2 2 2 140/90 22 WNL 14 7000 20 124 4.0 20 0.8 324 132 47 59 132 2
112

KEY TO MASTER CHART
Sl. No. Serial number
M/F Male/Female
DM-Dur Duration of diabetes (in years)
ND – Newly detected
Anti-DM Anti diabetic treatment
1 – on Insulin/OHA
2 – not on treatment
HTN Hypertension
1 – hypertensive
2 – normotensive
SM Smoking status
1 – smoker
2 – non smoker
BP Blood pressure
BMI Body mass index
Fundus WNL – normal
Hb% Haemoglobin
TC Total count
NPDR – non proliferative diabetic retinopathy
PDR – proliferative diabetic retinopathy
ESR Erythrocyte sedimentation rate
RBS Random blood sugar
HbA1c Glycosylated haemoglobin
113

FIB Fibrinogen
TCH Total cholesterol
HDL High density lipoprotein
LDL Low density lipoprotein
TG Triglyceride
MA Microalbuminuria
1 – present, 2 – absent
114