A STUDY OF THYROID DYSFUNCTION IN PATIENTS WITH

TYPE 2 DIABETES MELLITUS IN A TERITARY CARE

HOSPITAL

Thesis submitted in partial fulfillment of the rules

and regulations for the award of MD degree in
General Medicine, Kerala University of Health
Sciences

Dr.VIVEK KOSHY VARGHESE

Post graduate student, MD General Medicine, 2015-2018

DEPARTMENT OF GENERAL MEDICINE

SREE GOKULAM MEDICAL COLLEGE AND RESEARCH
FOUNDATION
2015– 2018
A STUDY OF THYROID DYSFUNCTION IN PATIENTS WITH
TYPE 2 DIABETES MELLITUS IN A TERITARY CARE
HOSPITAL

By

Dr.VIVEK KOSHY VARGHESE

Post Graduate Student in MD General Medicine

THESIS SUBMITTED IN PARTIAL FULFILLMENT OF

THE RULES AND REGULATIONS FOR THE MD DEGREE
EXAMINATION IN GENERAL MEDICINE

KERALA UNIVERSITY OF HEALTH SCIENCES

THRISSUR

2015– 2018
 DEPARTMENT OF GENERAL MEDICINE
SREE GOKULAM MEDICAL COLLEGE AND RESEARCH
FOUNDATION

CERTIFICATE

This is to certify that the thesis entitled “A STUDY OF

THYROID DYSFUNCTION IN PATIENTS WITH TYPE 2

DIABETES MELLITUS IN A TERITARY CARE HOSPITAL” is a

bonafide research work carried out by Dr.Vivek Koshy

Varghese, post graduate student, Department of General

Medicine, in partial fulfillment of the rules and regulations

for the award of MD Degree in General medicine.

Dr.V.Girija
Principal
 SreeGokulam Medical College

Date : and Research Foundation

Place :Venjaramoodu Venjaramoodu,
Thiruvananthapuram

DEPARTMENT OF GENERAL MEDICINE

SREE GOKULAM MEDICAL COLLEGE AND RESEARCH
FOUNDATION

CERTIFICATE
This is to certify that Dr.Vivek Koshy Varghese

has been a post graduate student in the department of

general medicine from 2015-2018. The thesis entitled

“A STUDY OF THYROID DYSFUNCTION IN PATIENTS WITH

TYPE 2 DIABETES MELLITUS IN A TERITARY CARE

HOSPITAL” is a bonafide research work carried out by

him in the department of general medicine, SreeGokulam

medical college and research foundation ,Venjaramoodu,

Thiruvananthapuram.
 Dr.Bhasi S
Professor and HOD
Department of general
medicine
Sree Gokulam medical
Date :
Place :Venjaramoodu college &
Research foundation.

DEPARTMENT OF GENERAL MEDICINE

SREE GOKULAM MEDICAL COLLEGE AND RESEARCH
FOUNDATION

CERTIFICATE BY THE GUIDE

This is to certify that the study entitled “A STUDY
OF THYROID DYSFUNCTION IN PATIENTS WITH TYPE 2
DIABETES MELLITUS IN A TERITARY CARE HOSPITAL” is
a bonafide research work carried out by Dr. Vivek Koshy
Varghese, under my direct guidance and supervision. All
 observations and conclusions have been made by the
candidate himself and have been checked by me
periodically.

Dr.Elizabeth Jacob
Associate professor
Department of
medicine

Date : SreeGokulam medical

Place :Venjaramoodu college and Research
foundation.

DEPARTMENT OF GENERAL MEDICINE

SREE GOKULAM MEDICAL COLLEGE AND RESEARCH
FOUNDATION

CERTIFICATE BY THE CO-GUIDE

This is to certify that the study entitled “A STUDY
OF THYROID DYSFUNCTION IN PATIENTS WITH TYPE 2
DIABETES MELLITUS IN A TERITARY CARE HOSPITAL” is
a bonafide research work carried out by Dr. Vivek Koshy
Varghese, under my direct guidance and supervision. All
observations and conclusions have been made by the
candidate himself and have been checked by me
periodically .

Dr. Tittu oommen

Assistant professor
Department of medicine

Date : SreeGokulam medical college

Place :Venjaramoodu
and Research
foundation.

DEPARTMENT OF GENERAL MEDICINE

 SREE GOKULAM MEDICAL COLLEGE AND RESEARCH
FOUNDATION

DECLARATION BY THE CANDIDATE

This is a consolidated report based on a bonafide study of

“A STUDY OF THYROID DYSFUNCTION IN PATIENTS WITH
TYPE 2 DIABETES MELLITUS IN A TERITARY CARE
HOSPITAL” done by me in the ,Departments of General
Medicine, SreeGokulam medical college and research
foundation ,Venjaramoodu , Thiruvananthapuram .This is
submitted to the Kerala University of Health Sciences in
partial fulfillment of the rules and regulations for the award
of MD Degree in General medicine.

Date : Dr. Vivek Koshy Varghese

Place :Venjaramoodu
 COPYRIGHT

Declaration by the Candidate

I hereby declare that the Kerala University of Health Sciences,

Thrissur shall have the rights to preserve, use and disseminate this
thesis in print or electronic format for academic / research purpose.

Date: Signature of the

Candidate
Place: Name
 ACKNOWLEDGEMENT

I would like to thank God Almighty for giving me an

opportunity to study on this topic and for being with me
during the whole study.
I am deeply indebted to my guide, Dr.Elizabeth Jacob,
Associate Professor and to my co-guide Dr Tittu Oommen ,
Department of Endocrinology, Sree Gokulam Medical
College and Research Foundation for their constant
guidance, support and valuable suggestions right from
making the abstract till completion.
I am indeed fortunate to have the support and counsel
of Dr.S.Bhasi, my Professor and HOD, Department of
General Medicine, Sree Gokulam Medical College and
Research foundation who was always supportive and
willing to help throughout the course of my study.
I would like to thank all the seniors, staff members of
the department of general medicine for their constant
support and guidance.
I would like to thank my brother Dr.Basil Paul manialil,
Assistant Professor Christain Medical College Vellore for
his help rendered in my thesis.
I would also like to thank Dr Nirmal George,
department of pharmacology for the help in statistical
analysis .
I wish to thank all patients and their family who were a
part of the study.
 I thank my father , mother , sister and my wife for
their love and support.
 TABLE OF CONTENTS

Title Page number

1 ABSTRACT

2 INTRODUCTION

3 OBJECTIVES

4 REVIEW OF LITERATURE & BACKGROUND

5 JUSTIFICATION

6 METHODOLOGY

7 RESULTS

8 DISCUSSION

9 CONCLUSION

10 BIBLIOGRAPHY AND REFERENCES

11 Annexures

Performa

Masterchart

Consent

Abbreviations
 LIST OF TABLES

Sl . No. Title of the table Page No.

1 Glucose Transporters 26

2 Classification of Diabetes 26

3 Symptoms of hyperglycaemia 28

4 Criteria For The Diagnosis Of Diabetes Mellitus 41

5 Categories of increased risk for diabetes (prediabetes) 42

6 Criteria for testing for diabetes or prediabetes in 43

asymptomatic adults
7 Glycemic recommendations for adults with diabetes 44

8 Physiological effects of thyroid hormone 45

9 Interpretation of thyroid hormones 46

10 Causes of hypothyroidism 47

11 Clinical features of hypothyroidism 48

12 Causes of hyperthyroidism 49

13 Clinical features of hyperthyroidism 50

14 WHO - Three grade classification system for goitre 51

15 Baseline parameters of the study participants 52

16 Age distribution of study participants 53

17 Anthropometric parameters analyzed based on gender 54

18 Body mass index of the study participants 55

19 Duration of type 2 diabetes mellitus among study 56

participants
20 Gender based analysis of blood glucose parameters 57
21 Symptoms of thyroid dysfunction in study participants 58

Sl.No. Title of table Page no:

22 Proportion of study participants with thyroid swelling 59

23 Gender based analysis of thyroid function among study 60
 participants
24 Anthropometric and laboratory parameters of study 61
participants with thyroid swelling (palpable & visible)
25 Comparison of anthropometric and laboratory parameters 62
between participants without goiter and with goiter
26 Thyroid dysfunction among study participants 63

27 Comparison of means based on participants thyroid 64

function
28 Association of gender and thyroid disorders of study 65
participants
29 Association of retinopathy and sub type of thyroid function 66
of study participants
30 Association of neuropathy and sub type of thyroid function 67
of study participants
31 Association of nephropathy and sub type of thyroid function 68
of study participants
32 Association of diabetic treatment with sub type of thyroid 69
function in study participants
33 Association of hypertension with sub type of thyroid 70
function among study participants
34 Association of ischemic heart disease and sub type of 71
thyroid function of study participants
35 Association of cerebrovascular accidents and sub type of 72
thyroid function among study participants
36 Association of thyroid swelling and sub type of thyroid 73
function among study participants
37 Association between symptoms of thyroid dysfunction and 74
sub type of thyroid status of study participants
38 Correlation of ADA glycemic goal and sub type of thyroid 75
function among study participants
39 Correlation of ADA glycemic goal and sub type of thyroid 76
function among study participants
40 77
 LIST OF FIGURES

Sl. No. Title of figure Page No.

1 Approach to management of diabetes

2 Diagnostic Stratergies for Hypothyroidism
3 Diagnostic Stratergies for Hyperthyroidism
4 Gender distribution of study participants

5 Body mass index of the study participants

6 Treatment regimens of diabetes mellitus among study
participants

7 Duration of type 2 diabetes mellitus among study

participants
8 Thyroid function among study participants

9 Demonstrating association of gender and type of

thyroid dysfunction

10 Association of thyroid status of participants and

retinopathy
11 Association of retinopathy and thyroid dysfunction of
study participants
12 Association of neuropathy and thyroid status of study
participants

13 Association of neuropathy and thyroid function of study

participants
14 Association of thyroid status of participants and
nephropathy
15 Association of nephropathy and thyroid dysfunction of
study participants
16 Association of diabetic treatment with thyroid disease
in study participants
17 Association of hypertension and thyroid status of study
participants
18 Association of hypertension with thyroid dysfunction in
study participants
SI. No Title of figure Page No

19 Association between ischemic heart disease and thyroid

status of study participants

20 Association of ischemic heart disease and thyroid

dysfunction in study participants

21 Association of cerebrovascular accidents and thyroid

status of study participants

22 Association of cerebrovascular accidents and thyroid

dysfunction in study participants

23 Association of thyroid swelling and thyroid status of

study participants
24 Association of thyroid swelling and thyroid dysfunction
among study participants

25 Association between symptoms of thyroid dysfunction

and thyroid disease of study participants
26 . Correlation of ADA glycemic goal and thyroid
dysfunction among study participants

27 Correlation of ADA glycemic goal and thyroid

dysfunction among study participants
ABSTRACT
Introduction and Objectives: Diabetes appears to influence thyroid function, firstly at
the level of hypothalamic in the control of TSH release and secondly in the peripheral
tissue, at the conversion of T4 to T3. This study determines the prevalence of Thyroid
dysfunction among Type 2 Diabetes mellitus and the proportion of thyroid disorders in
Type 2 diabetic patients.
Methodology: A prospective observational hospital based study. 150 type 2 diabetes
mellitus (T2DM) subjects were enrolled. These subjects were investigated for fasting
blood sugar (FBS), glycosylated haemoglobin (HbA1c), Thyroid involvement was
assessed using symptoms of thyroid dysfunction and based on laboratory values of total
triiodothyronine (T3), total thyroxine (T4), and thyroid-stimulating hormone (TSH). The
comparison of means of nominal variables between groups was done using independent
sample ‘t’ test and the comparison of ordinal variables between the groups were done
using Chi Square test.
Results: The mean age of the study participants was 60.1 ± 7.9 years. . The mean
duration of diabetes among the study participants was 13 ± 5.9 years. Mean glycosylated
haemoglobin (HbA1c) 7.7 ± 0.8 %. Prevalence of thyroid dysfunction in T2DM was
found to be 16.7%. The analysis revealed majority of the study participants as having
normal thyroid function (n=125, 83.3%), 20 participants (13.3%) with overt
hypothyroidism, 3 participants (2%) with subclinical hypothyroidism and 2 participants
(1.3%) with overt hyperthyroidism. Thyroid dysfunction was more in females as
compared to males that is 20 in 25 participants with thyroid disease were female.
Conclusion: The prevalence of thyroid dysfunction with T2DM (16.7%) and especially
hypothyroidism being more typical. Failure to recognise the presence of thyroid
dysfunction among T2DM patients may be a primary cause of poor management of
diabetes. We recommend screening and regular monitoring of thyroid dysfunction in
T2DM patients.

Keywords: Diabetes mellitus, Hypothyroidism, Hyperthyroidism

Introduction

Diabetes mellitus is a chronic endocrine disorder common in clinical

practice, It is the one of the leading cause of death worldwide. 1 It’s characteristic feature
is hyperglycemia resulting from various interactions of hereditary and environmental
factors and it may due to the combination of insulin resistance and defective secretion of
insulin by pancreatic β-cells or both. 2 The previous studies has shown impact of this
disease on the quality of life, and on morbidity and mortality through the complications
that affect the small and large vessels of the diabetes patients resulting in complications
like retinopathy, nephropathy, neuropathy, IHD, and large vessel obstruction has been
emphasized by study findings, the findings of the national commission (USA) on
diabetes and The Diabetes Control and Complications Trial( DCCT).3
Diabetes being the most seen endocrine metabolic disorder in clinical practise, there is a
curiosity to understand and learn the association of this with functions of another
common seen and documented endocrine gland that is thyroid gland. Prevalence of
thyroid disease reported in the previous studies were high in general population and is
only second to diabetes mellitus among all endocrine disorders. Previous studies
indicated there could be co-existence of the both the diseases. 4 Thyroid disorders and
Diabetes have a strong natural tendency to appear together in patients and this is due to
the interaction of thyroid hormones and Insulin. 5 6 Thyroid disease is common in the
general population, and the chances of thyroid disease increases with age. However
there is reported higher incidence of thyroid dysfunction in type 2 Diabetics than in the
general population.7

The thyroid hormones and Insulin are closely linked to cellular metabolism, so
that any alteration be it an increase or a decrease of any of these hormones will cause
functional derangement of the other, Thyroid dysfunction can cause both hypoglycaemia
and hyperglycaemia.8

Diabetes influence thyroid function at various levels like, control of TSH

release and in the peripheral tissue, at the conversion of T4 to T3. High uncontrolled
sugar result in reduction in the activity and hepatic concentration of T4-5-deiodinase,
low serum concentration of T3, increased levels of reverse T3 and low, normal, or high
level of T48–10.
 Since thyroid hormones regulate metabolism and diabetes can alter it, the
metabolism of organisms may be further affected by the combination of thyroid
dysfunction and diabetes.10
OBJECTIVES

To study the relationship between Type 2 diabetes mellitus and thyroid dysfunction.

To know the proportion of thyroid disorders in Type 2 diabetic patients.

To assess the need for annual screening of thyroid profile in Type 2 diabetic patients.
REVIEW OF LITERATURE

Historical review of Diabetes mellitus

Early description of diabetes was documented by Indian scholars since 1500

BC. They described it as “a mysterious disease causing thirst, increased urine output,
and wasting away of the body fat, and attracts flies and ants to urine of diabetic
patients”. The complete clinical detail of diabetes was first explained by physician
Aretaeus from Cappadocia. The word diabetes was first described by Apollonius of
Memphis around 250 BC, which means “to pass through” as the disease drains more
liquid than a person can take. Later , the Latin word “mellitus” was added because
the urine is sweet.11–13

Earlier in Indian literature this disease was named “Madhumeha” by

Susruta, Charaka and Vaghbata because of sweet taste of urine in polyuric patients ,
sticky to touch and ants were strongly attracted to it. They differentiated two forms of
the disease, one affecting thin people who do not survive long and the other, affecting
older and obese. They also described relation of diabetes to heredity, obesity, sedentary
life and diet. This description was parallel to the subdivision of diabetes into type 1 and
2 diabetes. Indian literature gets credit for the term “honey urine” referring to the clear
colourless nature of diabetic urine.14–16

Ancient Greek physicians adviced exercise which “employ moderate

friction”, preferable on horseback, to make less severe urination. Increase in wine intake
to compensate for loss of fluid weight, diet of starvation, therapy with potato, and
cure with oat were some of the other forms of treatment suggested for diabetes in
ancient times.11 Sir William Osler, in 1915, is said to have even recommended opium
for diabetic therapy. Early research linked diabetes to glycogen metabolism. The islet
cells of pancreas were discovered by Paul Langerhans, a young German medical
student.
In 1916, Sharpey-Shafer of Edinburgh suggested that a single chemical was
missing from the pancreas and named it as “insulin.” The term insulin originates from
the German word ”Insel “which means an islet or island.17
Historical review of Thyroid
The thyroid gland was explained from the time of Galen, earlier it was
thought that it provides fluid for the lubrication of the larynx. Wharton gave the name
‘thyroid’ from Greek word ‘thyroid’ which means Shield, and also considered that it
was designed by nature to provide especially in females a rotundity and beauty to the
neck. In Indian medicine literatures, Sushruta, Samhita at about 1400 BC mention about
goitre, hyperthyroiditis, and hypothyroidism. Andrecos Vesslius (1514-64) mentioned
thyroid gland as, having two lobes on each side of the root of the larynx which looks
like large fungus, flesh colour and is covered with blood vessels. Eustachius (1520-74
Ad) mentioned about the isthmus of the thyroid gland.18,19

In 1600 BC burnt sponge and seaweed had been used by Chinese for
goitre treatment. Scharge reported the blood supply of the thyroid gland. Alberchut
Von hallen (1768- 78) explained thyroid a ductless gland. Hippocrates and Plato in
the fourth century mentioned about a gland which is similar to thyroid gland, Pliny the
Elder in the first century referred to epidemics of goitre in the Alps and proposed
treatment with burnt seaweed, a practice also referred to by Galen in the second
century, regarding using burnt sponge for the treatment of goitre. Dendall of Mayo
clinic isolated the thyroid hormone, thyroxine in 1915. CR. Harrington (1925)
found out the chemical constitution and formulated means for artificial synthesis and
determined the principal chemical features responsible for specific physiological
activity (F Cuelly 1961).Endemic goitre were known to doctors of antiquity in India,
China and Greece.20,21

Epidemiology of diabetes

Globally, during the past two decades, the prevalence of diabetes increased
from an estimated number of 30 million cases in 1985 to 422 million in 2016. The
current trends, according to the International Diabetes Federation estimate about 438
million people will have diabetes by the year 2030. Although the prevalence of diabetes
is increasing globally, the prevalence of type 2 DM has increased more rapidly than type
1 DM, due to increasing risk factors like reduced activity because of industrialization,
obesity, and the aging of the world population.22, 23
 India became the country with the highest number of diabetic people (31.7 million) in
the year 2000, follows by china (20.8 million) then USA (17.7 million). Its predicted
that this values double by 2030 with (79.4 million) in India,(42.3 million) in China,
(30.3 million) in USA.24, 25

Geographic variation in the incidence of type 1 and type 2 DM is

documented. This is due to the different frequency of high-risk human leukocyte
antigen (HLA) alleles among ethnic groups in different geographical locations. In type 2
DM and Impaired Glucose tolerance, this variability is because of genetic, behavioural,
and environmental factors. The prevalence of diabetes also varies among different ethnic
populations within a country. The onset of type 2 DM occurs, at an earlier age in certain
ethnic groups . In India, the prevalence of diabetes is increasing rapidly with the onset of
lower BMI and younger age, greater visceral adiposity, and reduced insulin secretion. 26,
27

PREVALENCE OF THYROID DYSFUNCTION

According to various studies 42 million people in India have thyroid
disorders, of which hypothyroidism is most common affecting one in ten adults. The
prevalence of hypothyroidism in a recent population based study in Cochin was 3.9%
and prevalence of subclinical hypothyroidism was 9.4% compared with only 2% in the
UK and 4·6% in the USA. Comparing coastal cities like Mumbai, Goa, and Kerala with
cities located inland like Kolkata, Delhi, Ahmedabad, Bangalore, and Hyderabad
coastal cities have a higher prevalence (11·7% vs. 9·5%).15, 16

The reason behind the higher mean thyroid stimulating hormone

concentration and range in India compared with western countries is due to long-
standing iodine deficiency in the country, which has only been partly corrected over the
past 20 years. The highest prevalence of hypothyroidism (13·1%) is seen in age group
46–54 years, with people aged 18–35 years being less affected (7·5%). In women it’s
11.4% compared to men 6.2%. 53% of subclinical was positive for anti-TPO
antibodies . In an epidemiological study from Cochin prevalence of subclinical
hyperthyroidism was 1.6% and that of overt hyperthyroidism was 1.3%. Recent
population study showed that about 12% have palpable goiter.29, 30
Diabetes mellitus

According to WHO Diabetes is defined as a chronic disease that occurs

either when the pancreas does not produce enough insulin or when the body cannot
effectively use the insulin it produces.31

Glucose-metabolism
Blood glucose levels are closely regulated in the range of 3.5–8.0
mmol/L (63–144 mg/dL), inspite of varying demands of food, fasting and exercise.
The main organ of glucose homeostasis is the liver, which absorbs and stores
glucose (as glycogen) in the post-absorptive state and releases it into the
circulation between meals to meet the rate of glucose utilization by peripheral
tissues. It also synthesizes glucose molecule by the process of gluconeogenesis. 18,
19

Glucose-production
About 200 g of glucose is produced and utilized each day. More than
90% is derived from liver by glycogenolysis and gluconeogenesis, and the
remainder from renal gluconeogenesis.34–36

Glucose utilization

The brain is the prime consumer of glucose and its function depends
on an uninterrupted supply of glucose. Its requirement is 1 mg/kg/min, or 100 g
daily in a 70 kg person. Glucose uptake by the brain is mandatory for survival
and is not insulin dependent, and it’s oxidized to carbon dioxide and water.
Tissues like muscle and fat depends on insulin-responsive glucose transporters for
glucose absorbtion in response to postprandial peaks in glucose and insulin. At
other times, energy requirements are depends on fatty-acid oxidation. In the
muscle glucose which is taken up is stored as glycogen or metabolized to
lactate or carbon dioxide and water. Fat utilizes glucose as a substrate for
triglyceride synthesis; lipolysis releases fatty acids and glycerol from triglyceride,
of which glycerol is a substrate for hepatic gluconeogenesis.37, 38

Insulin structure and secretion

 Insulin is the main hormone involved in the storage and controlled
release within the body of the chemical energy available from food. It is linked
with chromosome 11 and produced in the β cells of the pancreatic islets.
Following secretion, it enters the portal circulation and goes to liver, its main
target organ, where 50% of secreted insulin is extracted and degraded ; the residue
of which is broken down by the kidneys. C-peptide is only partially extracted by
the liver (hence provides a useful index of the rate of insulin secretion) but is mainly
degraded by the kidneys.39

Hormonal-regulation
Insulin is a prime regulator of intermediary metabolism, and its
actions are modified in many respects by other hormones. Its actions are also
different in the fasting and postprandial states. In the fasting state, it regulates
glucose release by the liver, and in the postprandial state it facilitates glucose
uptake by fat and muscle. The role of counter-regulatory hormones [glucagon,
adrenaline (epinephrine), cortisol and growth hormone] are hepatic gluconeogenesis
and reduce its utilization in fat and muscle for a given level of insulin. 40
Table 1 Glucose transports37,41

• GLUT-1 facilitate basal non-insulin stimulated glucose uptake into

many cells

• GLUT-2 as a prerequisite for glucose sensing, transport glucose into

the β cell of pancreas and is also present in the renal

tubules and hepatocytes.

GLUT-3 promotes non-insulin mediated glucose uptake into brain

neurones and placenta.

GLUT-4 promotes major peripheral action of insulin. It is through

this channel glucose is taken up into muscle and adipose

tissue cells following stimulation of the insulin receptor

The insulin receptor

This is a glycoprotein (400 kDa), linked with the short arm of

chromosome 19, which straddles the cell membrane of many cells. It is a dimer

with two α-subunits, which contain the binding sites for insulin, and two β-

subunits, which traverse the cell membrane. When insulin binds to the α-subunits,

it results in a conformational change in the β-subunits, causes activation of

tyrosine kinase which results in a cascade of response involving a host of other

intracellular substrates. One such response is migration of the GLUT-4 glucose

transporter to the cell surface and increased transport of glucose into the cell,

following which the insulin-receptor complex is internalized by the cell, insulin is

degraded, and the receptor is recycled to the cell surface.42–44

Table 2 CLASSIFICATION OF DIABETES 45

Type 1 diabetes Type 2 diabetes Gestational diabetes Specific types due to

mellitus (GDM) other causes,

autoimmune b- progressive loss diabetes diagnosed -monogenic diabetes

cell destruction, of b-cell insulin in the second or third syndromes -such as

usually leading to secretion trimester of neonatal diabetes and

absolute insulin frequently on the pregnancy that was maturity-onset diabetes

deficiency background of not clearly overt of the young( MODY]),

insulin resistance diabetes prior to diseases of the exocrine

gestation pancreas - cystic

fibrosis

- Drug- or chemical

induced diabetes -such

as with glucocorticoid
Table 3 Symptoms of hyperglycaemia

Symptoms

• Thirst, dry mouth

• Polyuria

• Blurring of vision

• Pruritus vulvae, balanitis (genital candidiasis)

• Nausea

• Headache

• Hyperphagia; predilection for sweet foods

• Mood change, irritability, difficulty in concentrating, apathy Nocturia

• Tiredness, fatigue, lethargy

• Change in weight (usually weight loss)

Diagnosis and investigations

Table 4 —Criteria For The Diagnosis Of Diabetes Mellitus(ADA 2015)45

Symptoms of DM plus random blood glucose more than or equal to 200MG/dl

or

Fasting blood glucose more than or equal to 126mg/dl

or

HbA1C more than or equal to 6.5%

or
2hour blood glucose more than or equal to 200mg/dl after glucose tolerance test

Pre-diabetes

Table 5 Categories of increased risk for diabetes46 (prediabetes)*

FPG100mg/dL(5.6mmol/L)to125mg/dL(6.9mmol/L)(IFG)

OR

2-h PG in the 75-g OGTT 140 mg/dL (7.8 mmol/L) to 199 mg/dL (11.0

mmol/L) (IGT) OR

A1C 5.726.4% (39247 mmol/mol)

*For all three tests, risk is continuous, extending below the lower limit of the range and

becoming disproportionately greater at the higher end of the range.

Impaired glucose tolerance

Impaired glucose tolerance (IGT) is not a clinical entity but have an increased

risk for future diabetes and cardiovascular disease , which is same as for frank

diabetes but do not develop the specific micro vascular complications.

The diagnosis can only be made from glucose tolerance test. The group is

heterogeneous; either patients are obese, or have liver disease or are on

medication that impairs glucose tolerance47,48.

Impaired fasting glucose

This diagnostic category include (fasting plasma glucose between 6.1 and 6.9

mmol/L) It is not a clinical entity but indicates future risk of frank diabetes and
cardiovascular disease. A lower cut-off of 5.6 mmol/L (rather than 6.1 mmol/L)

has been recommended by the ADA.49–51

Haemoglobin A1c

Haemoglobin A1c (HbA1c) provides the integrated measure of an individual's

blood glucose concentration over several weeks.

According to ADA HbA1c of >6.5% (48 mmol/mol) is diagnostic of diabetes,

whereas a level of 5.7–6.4% (39–46 mmol/mol) is considered increased risk of

diabetes. A WHO also considers HbA1c as a diagnostic test for diabetes. The

ADA has recommended that HbA1c should be used together with IGT and IFG

as a marker of ‘pre-diabetes’, with a range of 5.6–6.4% (38–46mmol/mol).52,53

Table 6—Criteria for testing for diabetes or prediabetes in asymptomatic adults54

Testing should be considered in overweight or obese adults who have one or more

of the following risk factors:-A)Hb A1C ≥5.7% (39 mmol/mol), B)first-degree

relative with diabetes high-risk race/ethnicity (e.g., African American, Latino,

Native American, AsianAmerican, Pacific Islander) C)women who were diagnosed

with GDM, D) history of CVD, E) hypertension, F)HDL cholesterol level ,35 mg/dL

(0.90 mmol/L) and/or a triglyceride level .250 mg/dL(2.82 mmol/L) G) women with

polycystic ovary syndrome H) physical inactivity. I)Insulin resistance (e.g., severe

obesity, acanthosis nigricans).

2. testing should start at age 45 years.

3. If normal, testing should be repeated at 3-year intervals, with consideration of

 more frequent testing depending on initial results (e.g., those with prediabetes

should be tested yearly) and risk status.

Table 7 Recommendations for Glycemic control in adults with diabetes

HbA1C , <7.0% (53 mmol/mol)

Preprandial capillary plasma glucose 80–130 mg/dL (4.4–7.2 mmol/L)

Postprandial capillary plasma glucose, < 180 mg/dL (10.0 mmol/L)

Figer 1 55
Modulation of the strictness of glucose lowering in type 2 diabetes. Depiction of patient

and disease factors may be used by the general practitioner to determine optimal

HbA1c targets in type 2 diabetes patients . Regarding a particular domain are represented

by increasing height of the corresponding slope. Thus, characteristics towards the left

justify more strict efforts to lower HbA1c, whereas those toward the right suggest less

strict efforts. Where possible, such decisions should be made with the patient, reflecting

his or her preferences, needs, and values55.

The Thyroid Axis

The metabolism of virtually all nucleated cells of many tissues is controlled by the

thyroid hormones. Over activity or under activity of the gland is the most common

of all endocrine problems.56

Anatomy

The thyroid gland has two lateral lobes connected by an isthmus. It is attached

to the thyroid cartilage and to the upper end of the trachea, and thus moves on

deglutition. It originates from the base of the tongue and descends to the middle

of the neck. Remnants of thyroid tissue can sometimes be seen at the base of the

tongue (lingual thyroid) and along the line of descent. The gland is supplied by

superior and inferior thyroid arteries. The thyroid gland consists of follicles lined

by cuboidal epithelioid cells, which contains colloid (the iodinated glycoprotein

thyroglobulin), synthesized by the follicular cells. Each follicle is surrounded by

basement membrane, and between them contains Para follicular cells ( calcitonin-

secreting C cells)57–60

Physiology

The thyroid gland synthesizes two hormones, triiodothyronine (T3) which acts at

the cellular level and L-thyroxine (T4), a prohormone which is converted in some

peripheral tissues (liver, kidney and muscle) to the more active T3 by 5′-

monodeiodination; an alternative 3′-monodeiodination yields the inactive reverse T3

(rT3). In severe non-thyroidal illness, more T4 than T3 is produced. Inorganic

iodide trapped by the gland is oxidized and incorporated into the glycoprotein

thyroglobulin to form mono and diiodotyrosine, and then T4 and T3, by an

enzyme-dependent system.61–63

More than 99% of the thyroid hormones are bound to hormone-binding

proteins (thyroxine binding globulin, TBG; thyroid-binding prealbumin, TBPA;

and albumin) in the plasma and only free hormone is available for action

in the target tissues. T3 binds to specific nuclear receptors within target cells.

Most laboratories now measure free T4 levels since many drugs and other

factors affect TBG; all may result in confusing total T4 levels in blood.64,65

Control of the hypothalamic–pituitary–thyroid axis

Hypothalamus secrete a peptide hormone Thyrotrophin-releasing hormone (TRH),

which in turn stimulates the pituitary to secrete thyroid-stimulating hormone

(TSH) . TSH acts on the thyroid gland which, stimulates growth and activity of

the thyroid follicular cells via the G-protein-coupled TSH membrane receptor ,

which subsequently secretes T3 and T4 hormones into the circulation and then
exert negative feedback on the hypothalamus. Circulating T4 is peripherally

deiodinated to T3, which is the active form that binds to the thyroid hormone

nuclear receptor (TR) on target organ cells to cause modified gene transcription.

The tissue-specific effects of T3 are dependent upon the local expression of these

TR receptors. There are two forms of TR receptors (TR-α and TR-β) . High T4

levels in the presence of inappropriately normal circulating TSH, suggest a

role for TR receptors in thyroid hormone resistance66–69.

Overt hypothyroidism

It is defined as a clinical syndrome of hypothyroidism associated with elevated TSH

(>4.2μU/ml) and decreased serum levels of T4 (<5.1 μg/dl) or T3 (<0.8 ng/ml)70

Subclinical hypothyroidism

It is defined as a condition without typical symptoms of hypothyroidism, elevated TSH

(>4.2 μU/mL), and normal circulating thyroid hormones71.

Overt hyperthyroidism

It is defined as a condition with elevated T3 (>2.0 ng/ml) and T4 (>14.1 μg/dl) TSH

<0.1 μU/ml with symptoms of hyperthyroidism72.

Subclinical hyperthyroidism

It is defined as a condition without typical symptoms of Hyperthyroidism, decreased

TSH (< 0.1 μU/mL), and normal circulating thyroid hormones73.

Table 7 Physiological effects of thyroid hormone74,75

Target Effect

Cardiovascular system Increases heart rate and cardiac output

Bone Increases bone turnover and resorption

Respiratory system Normal hypoxic and hypercapnic drive in respiratory centre

Gastrointestinal system Increases gut motility

Blood Increases red blood cell 2,3 -bisphosphoglyceric acid,

facilitating oxygen release to tissues

Neuromuscular function Increases speed of muscle contraction/relaxation and

muscle protein turnover

Carbohydrate metabolism Increases hepatic gluconeogenesis/glycolysis and

intestinal glucose absorption

Lipid metabolism Increases lipolysis and cholesterol synthesis and degradation

Sympathetic nervous Increases catecholamine sensitivity and β-adrenergic receptor

system numbers in heart, skeletal muscle, adipose cells and

lymphocytes, Decreases cardiac α-adrenergic receptors

Dietary iodine requirement

Worldwide, dietary iodine deficiency is a major cause of thyroid disease,

since it’s essential for thyroid hormone synthesis. The recommended daily
intake of iodine should be at least 140 µg, and iodination of salt has reduced

the number of thyroid patients in areas where ‘endemic goitre’ still occurs76,77.

Investigations

Immunoassays of Thyroid function test for T4, T3 and TSH .Usually Minor

circadian rhythms in hormone level exist and therefore measurements may be

made at any time.78

Table 8 Interpretation of thyroid hormones79

TSH T3 T4

(0.1 -4.2 microIU/ml) (0.8-2 ng/ml) (5.1-14.1

microg/dl)

Thyrotoxicosis Suppresed Increased Increased

Primary Increased Low/Low- Normal or

hypothyroidism normal low

TSH deficiency Low-normal or Low/Low- Normal or

subnormal normal low

T3 toxicosis Suppressed normal Increased

Compensated Slightly increased normal normal

euthyrodism
TSH measurement

TSH levels helps to differentiate between hyperthyroidism, hypothyroidism and

euthyroidism (normal thyroid gland function), Except in case of hypopituitarism,

and the ‘sick euthyroid’ syndrome where low levels of TSH (which normally

indicates hyperthyroidism) occur in the presence of low or normal T4 and

T3 levels. So as a single test of thyroid function, TSH measurement is the

most sensitive , but for correct diagnosis two tests are required: for example,

TSH plus free T4 or free T3 if hyperthyroidism is suspected; TSH plus

serum free T4 in case of hypothyroidism80,81 .

TRH test

This test is done for investigation of hypothalamic–pituitary dysfunction. In

case of raised fT4 and TSH, TRH (protirelin) is used . Following TRH

administration, there is a rise in TSH in thyroid hormone resistance, while in

TSHoma TSH response is same due to continued autonomous TSH secretion,

which does not respond to TRH.82

Difficulties in thyroid function test interpretation

Systemically ill patients can have an apparently low total and free T4 and T3

with a normal or low basal TSH (the ‘sick euthyroid’ syndrome) due to reduced

concentration and affinity of binding proteins, decreased peripheral conversion of

T4 to T3 with more rT3 and reduced hypothalamic–pituitary TSH production.

Therefore the tests should be repeated after resolution of the underlying illness.

In pregnancy there is increased TBG levels and high or high-normal total

T4. Free T4 is usually normal. Normal ranges of free T4 and TSH alter with the

normal physiological changes during pregnancy.83

Many drugs affect thyroid function tests by interfering with protein binding.

Amiodarone causes hyper and hypothyroidism and also decreases T4 to T3

conversion and therefore free T4 levels may be above normal in a euthyroid

patient thus TSH level is usually reliable.83

Hypothyroidism

It refers to a condition produced due to under activity of thyroid gland resulting in

deficiency of thyroid hormone. Under activity of the thyroid gland may be

primary, caused by disease of the thyroid, or secondary to hypothalamic–

pituitary disease (reduced TSH drive). 84

Table 9 Causes of hypothyroidism85

Primary Secondary

Defects of hormone synthesis Hypopituitarism

• Iodine deficiency • Isolated TSH deficiency, TSH ( thyroid-

• Antithyroid drugs stimulating hormone.) Peripheral resistance to

• Dyshormonogenesis thyroid hormone

Congenital

• Agenesis

• Ectopic thyroid remnants

Infective

• Post sub-acute thyroiditis

Post-irradiation

• Radioactive iodine therapy

Autoimmune

• Atrophic thyroiditis

• Hashimoto's thyroiditis

Infiltration

• Tumour
Table 10 Clinical features of hypothyroidism86

Signs Symptoms

Periorbital oedema Depression

Deep voice Deafness
Myotonia Poor libido
Psychosis/dementia Puffy eyes Coma
Mental slowness Poor memory
Ataxia Constipation
Poverty of movement Anorexia
Deafness Trirdness / Malaise
Dry thin hair Weight gain
Loss of eyebrows Cold intolerance
Hypertension Change in appearance
Hypothermia
Proximal Myopathy

Difficulties in diagnosis may arise in certain circumstances:

Children with hypothyroidism do not show classic features . They present with

slow growth velocity, poor school performance and sometimes arrest of pubertal

development.Young women with hypothyroidism do not show obvious signs.

Thyroid function should be evaluated in young women presenting with

oligomenorrhoea/amenorrhoea, menorrhagia, infertility or hyperprolactinaemia.

The elderly show many clinical features that are difficult to differentiate from

normal ageing, but specially look for hypothyroidism in elderly presenting

with cognitive impairment.87

Figer 2 Diagnostic Stratergies for Hypothyroidism88
Hyperthyroidism

Hyperthyroidism is a condition in which there is more production of thyroid hormone.

Thyrotoxicosis is a toxic condition that is caused by excess of thyroid hormone of any

cause. Prevalence is 2–5% of the population, more common in females in the ratio of

5:1; common age group affected documented are 20 to 40 years. More than 99% of

cases are caused by intrinsic thyroid disease; a pituitary cause is extremely rare.89

Table 11 Causes of hyperthyroidism90

Common Uncommon Rare

• Toxic multinodular • Acute thyroiditis • Metastatic differentiated

goitre – Viral (e.g. de Quervain's) thyroid carcinoma

• Graves' disease – Autoimmune • TSH-secreting pituitary

(autoimmune) – Post-irradiation tumours

• Solitary toxic – Postpartum • HCG-producing tumour.

nodule /adenoma • Exogenous iodine

• Drugs – amiodarone

• Thyrotoxicosis factitia

(secret T4 consumption)

• Gestational thyrotoxicosis

(HCG-stimulated)

• Neonatal thyrotoxicosis

(maternal thyroid antibodies)

Table 12 Clinical features of hyperthyroidism91

Symptoms Signs

Palpitations Tremor

Eye complaints Exophthalmose

Thirst Hyperkinesis

Vomiting Tachycardia

Diarrhoea Atrial fibrillation

Heat intolerance Warm vasodilation peripheries

Stiffness Onycholysis

Weight loss Palmar erythema

Irritability/behaviour change Weight loss

Restlessness Thyroid acropachy

Malaise Lid lag and ’ stare’

Itching Conjunctival oedema

Sweating Proximal myopathy

Muscle weakness Proximal muscle wasting

Tremor

Choreoathetosis

Gynecomastia

Oligomenorrhoea
Figer 3 Diagnostic Stratergies for Hyperthyroidism92
PREVALENCE OF THYROID DYSFUNCTION IN TYPE 2 DIABETICS

Nobre et al. Retrospective study in Portugal reported that there are few studies on DM2

and thyroid dysfunction; they seem to indicate a higher occurrence of thyroid

dysfunction among diabetics when compared with the general population93.

Patricia wu in her article has stated the prevalence of thyroid disease in Diabetics has

been estimated at 10.8% with most cases being hypothyroidism at 30% and subclinical

hypothyroidism at 50%. Hyperthyroidism on the other hand accounts for 12% and

postpartum thyroiditis for 11 %.94 Chubb et al Diabetes study found a prevalence of

subclinical hypothyroidism of 8.6% in women with Type 2 Diabetes. 95

Papazafiropoulou et al in his cross-sectional study explained the prevalence of thyroid

dysfunction among Greek diabetic population is 12.3% 96. Diabetic women were more

frequently affected than men Radaideh et al. study reports 5.9% of diabetic patients

were known to have thyroid disease, new thyroid disease cases were diagnosed in 6.6%

of the patients and the prevalence of autoimmune thyroid disease in type 2 Diabetes and

reported it to be 12.5%.97. Gambelunghe et al. stated the notable increased risk of

thyroid disease in adult type 2 diabetics, which have been confirmed in pediatric

group.32, 33 Uzunulu et al. commented that the prevalence of subclinical hypothyroidism

is higher in patients with metabolic syndrome than in non-metabolic syndrome subjects

due to the presence of obesity, Hypertension, Insulin resistance and deranged lipid
100
concentrations . Cardoso et al. study on thyroid dysfunction in diabetic patients, a

Cross-sectional study which reported thyroid dysfunction and autoimmunity are

common in patients diagnosed as diabetes 101. Akbar et al. stated that further studies are

needed to evaluate the cost effectiveness of thyroid screening in diabetics 102. Vikram et

al. cross-sectional study in India reported the prevalence of thyroid dysfunction in type
2 DM population is 30 % were subclinical hypothyroidism is being most common. He

also stated that patients with type 2 DM have to be screened for thyroid dysfunction to

reduce the percentage of mortality rate103. Perros et al cross-sectional study in Scotland

stated that female patients with diabetes had the increased annual risk of developing

thyroid dysfunction, but all group of patient has increased incidence of thyroid

dysfunction, compared to that reported in the general population. Study also suggests

that thyroid function should be screened annually in diabetic patients to detect

asymptomatic thyroid dysfunction which is increased in frequency in a diabetic group104.

Pasupathi et al. in their cross sectional study investigated the adverse effects of diabetes

on thyroid hormone levels and other biochemical variables in diabetic patients.

Out of 100 diabetic patients studied, 28% had low thyroid hormone, 17% had high

thyroid hormone, and 55% had euthyroid hormone levels105. Udiong et al in their Cross

sectional study report of 161 diabetic subjects, 26.6% has low plasma thyroid hormone

levels (FT4>2.01ng/dl), 19.8% has raised plasma thyroid hormone levels (FT4 < 2.01),

and 54% was euthyroid (FT4 0.78 - 2.01ng/dl). This study had shown a high incidence

(46.5%) of abnormal thyroid hormone levels among the diabetics (hypothyroidism

26.6%,hyperthyroidism,19.9%)106.

EFFECT OF DIABETES ON THYROID FUNCTION

Schlienger et al. in their study where base line plasma levels of thyroxine (T4),

triiodothyronine (T3) and reverse T3 were evaluated by radioimmunoassay in 44 control

subjects, 44 Type 1 diabetes patient and 39 Type 2 diabetic patients aged from 15 to 75

years. All the patients were clinically euthyroid. The quality of diabetic control was

assessed by the percentage of glycosylated haemoglobin. In both the diabetic patient

groups there were a significant decrease in T3 and a rise in reverse T3 whereas T4 was
normal. They found no significant differences between plasma thyroid hormone levels

in Type 1 and Type 2 diabetic groups. Poorly controlled diabetes influences serum T3

levels, basal TSH levels and TSH response to thyrotropin releasing hormone (TRH). In

the diabetic group without associated illness, a negative linear correlation was found

between T3 and glycosylated haemoglobin and a positive correlation between reverse

T3/T3 and glycosylated haemoglobin. No correlation between T3 or reverse T3 and

fasting blood glucose could be established. In conclusion, most of the diabetic patients

showed a low T3 suggesting possibility of an impairment in the extrathyroidal

conversion of T4 to T3. This may well be enhanced by a poor diabetic control107.

Kabadi et al. stated that uncontrolled diabetes mellitus is a state in which glucose does

not enter the cells causing cellular starvation and hyperglycemia. Therefore, serum T4,

T3, rT3,TSH, and glucose were determined after an overnight fast in 94 male diabetics

during a routine follow-up visit to the outpatient clinic and 24 healthy male adults.

HbA1c were measured in normal individuals and 16 newly noticed diabetic patients. In

normal individuals, no significant relationships between fasting plasma glucose and T3

and rT3 levels were observed. In diabetics there was a significant positive correlation

between glucose and rT3. In the study diabetics patients, with uncontrolled diabetes,

serum T3 raised and rT3 declined on improvement of hyperglycaemia. Glycosylated

haemoglobin levels decreased as well. These reviewed study state that thyroid hormone

metabolism is usually altered in diabetes mellitus with a decrease in serum T3 and a

reciprocal elevation in rT3. The T3 and rT3 concentrations may help as an indicators of

glycaemic control in diabetes mellitus108.

Both Type 1 and Type 2 diabetes when poorly controlled cause a low serum total and

free T3 levels, increase in rT3( reverse T3), near normal serum TSH and T4 levels by

reduction in peripheral conversion of thyroxin (T4) to tri-iodothyronine (T3) via

5’monodeiodination reaction.109 The long term diabetic control determines the plasma

T3 levels as evidenced by previous studies. It also cause impaired TSH response to TRH

or loss of normal nocturnal TSH peak. Of there,TSH responses and low T3 levels

may normalize with good glycemic control. However, the normal nocturnal peak of

TSH is not restored in patients with totally absent pancreatic beta cell function. 110

EFFECT OF HYPERTHYROIDISM ON GLYCEMIC STATUS

In hyperthyroidism, Graves Disease is the commonest etiology. Up to 50% of patients

with Grave’s disease have been noted to have variable glucose intolerance. This has also

been noted in 2-3% of patients with diabetes, when hyperthyroidism develops in

previously euglycemic individuals. Development of hyperthyroidism in known diabetic

patients herald the deterioration of diabetic control. This deterioration may be attributed

to the various metabolic changes that occur. Some of this changes include accelerated

gastric emptying, enhanced intestinal glucose absorbtion and increase in portal venous

blood flow in the gastrointestinal system.109 Hyperthyroidism by itself causes decreased

insulin secretion 111,112 or normal or increased levels of insulin in the peripheral and

portal circulation.113 The increased degradation of insulin may cause masking of the

increased insulin secretion. The insulin clearance rate is increased by about 40% in

hyperthyroidism.114 Long term thyrotoxicosis cause beta cell dysfunction resulting in

reduced pancreatic insulin response to glucose and decreased insulin secretion rate. 115

EFFECT OF HYPERTHYROIDISM

When euglycemia individuals develop hyperthyroidism, 2-3% of these may become

diabetic and cause increase in thyroid hormone resembles sympathetic nervous system

over activity and includes increased heart rate, tremor and excessive sweating. This

over activity causes hypoglycaemia unawareness in diabetes.116If pre-existing Graves

Orbitopathy is present, the risk of visual loss is increased and chances of visual

recovery are bleak with the presence of diabetes.117 Thyrotoxicosis can induce many

cardiac effects such as systolic hypertension, sinus tachycardia, changes in ventricular

systolic and diastolic function, and predisposition to dysrhythmias, particularly atrial

fibrillation.118

EFFECT OF DRUGS ON THYROID FUNCTION

Many classes of drugs affect thyroid hormone balance first and second generation,

preexisting thyroid dysfunction worsen with the use of oral hypoglycemic. The first

generation sulfonylureas like chlorpropamide, carbutamide inhibit binding of

(Thyroxine) T4 and (Triiododthyronine) T3 to TBG competitively hence affect

peripheral thyroid function and they also inhibit thyroid hormone synthesis. Similar

report has been made of effect of second generation sulfonylureas. Many of the type 2

diabetes individuals on Metformin were found to have reduced TSH levels, while

Orbitopathy is the complications noticed in patients on Thiazolidinediones. Due to the

fact that patients with diabetes are prone for other complications. Type 2 diabetes

patients on Amiodarone for Arrhythmias are prone to developing either

hyperthyroidism or hypothyroidism as it inhibits peripheral conversion of T4 to T3,

clearance of T3 and T4, direct cytotoxic effect on thyroid follicular cells and its

metabolite, amiodarone acts a competitive antagonist of T3 cellular level in cardiac. 119,120

OUTCOME OF TREATMENT OF THYROID DYSFUNCTION

In a study by Beciragic et al.121 and Velija et al.122 a cohort of type 2 Diabetes

patients with subclinical hypothyroidism and subjected to low dose of thyroxine at

25ug. At 1 month and 6 months after treatment, there was sustained reduction in levels

of HbA1C, fasting and post prandial glucose levels, fasting Insulin levels, levels of C
reactive Proteins and levels of total cholesterol and triglycerides. On the other hand, in

yet another study Al Shoumer et al.123 and Ficaet al.124 in a cohort study of patients with

concomitant Diabetes and hyperthyroidism and treated them with Carbimazole .They

noted that with stabilization of thyroid function; levels of HbA1c, fasting insulin and pro

insulin levels were markedly reduced, as well as amount of Insulin needed to control

Diabetes reduced after patient became euthyroid.

JUSTIFICATION OF STUDY

Diabetes mellitus is a major health problem affecting larger populations

worldwide. Despite the very long steps made in management of Diabetes, large number
of patients still present with complications due to poor glycaemic control. The
underlying thyroid disorders may go undiagnosed because the common signs and
symptoms of thyroid disorders are similar to those for diabetes and can be overlooked or
attributed to other medical disorders. Thyroid dysfunction have been reported in
previous studies contribute to significant morbidity in the general population and is
particularly increased in type 2 Diabetics.

The benefit of early identification of both diseases has a significant

impact on improving cardiovascular function, blood pressure, and lipid profile, thereby
reducing long-term cardiovascular risk and improving quality of life for persons with
diabetes. There is shortage of data on thyroid dysfunction in type 2 diabetics in our
population, implying the burden of the same may be over or under estimated. This study
may helpful for future studies which can support screening and management of thyroid
dysfunction to achieve glycemic control in type 2 diabetics.
METHODOLOGY

OPERATIONAL DEFINITION

In this study, study subjects were subjects attending outpatient and

inpatient department of Sree Gokulam Medical College and Research Foundation,
Venjaramoodu. Diagnosis of Diabetes was done using ADA 2015

CRITERIA FOR THE DIAGNOSIS OF DIABETES MELLITUS125

1. Symptoms of DM plus random blood glucose more than or equal to 200MG/dl or
2. Fasting blood glucose more than or equal to 126mg/dl or
3. HbA1C more than or equal to 6.5% or
4. 2hour blood glucose more than or equal to 200mg/dl after glucose tolerance test

Table 13 WHO - Three grade classification system for goitre126,127

Grade Characteristics
0 No palpable or visible goitre.
1 A goitre that is palpable but not visible
when the neck is in the normal position
(i.e. the thyroid gland is not visibly
enlarged). Nodules in a thyroid that is
otherwise not enlarged fall into this
category.
2 A swelling in the neck that is clearly
visible when the neck is in a normal
position and is consistent with an enlarged
thyroid gland when the neck is palpated.

Overt hypothyroidism was defined as a clinical syndrome of hypothyroidism

associated with elevated TSH (>4.2μU/ml) and decreased serum levels of
T4 (<5.1 μg/dl) or T3 (<0.8 ng/ml).
Subclinical hypothyroidism is defined as a condition without typical symptoms of
hypothyroidism, elevated TSH (>4.2 μU/mL), and normal circulating thyroid
hormones.128
Overt hyperthyroidism is defined as a condition with elevated T3 (>2.0 ng/ml) and
T4 (>14.1 μg/dl) TSH <0.1 μU/ml with symptoms of hyperthyroidism.129
Subclinical hyperthyroidism is defined as a condition without typical symptoms of
Hyperthyroidism, decreased TSH (< 0.1 μU/mL), and normal circulating thyroid
hormones.129
MATERIALS & METHODS
STUDY DESIGN:
Prospective Observational Study

STUDY SETTING:

Department of General Medicine, Sree Gokulam Medical College & Research

Foundation.

STUDY POPULATION:

Subjects attending outpatient and inpatient Department of General Medicine, Sree

Gokulam Medical College & Research Foundation.

STUDY SUBJECTS:
Cases were subjects with diagnosis of Type 2 diabetes mellitus-attending to OPD/IPD in
SGMC & RF, Trivandrum can be taken as cases in the study after obtaining informed
consent from them.

SAMPLE SIZE:
As per research publications, prevalence of thyroid disorders among diabetic varies. The
following table demonstrated the same.
Akbar et al.102 10%
Perros et al.104 13.4%
Radaideh et al.97 12.5%
Diez et al.130 32%
Anil Kumar et al.131 24%
Ravishankar et al.132 29%
Vikram et al.133 30%
 From the above references, it can be concluded that the prevalence ranges from
10 to 32 percent.Hence for this current study, prevalence of thyroid dysfunction among
diabetic population is taken as 20 % for the calculation of study population. So sample
size for the current study can be calculated by using reference from above mentioned
studies.
The values taken are Confidence level of 95 percent, Allowable error between
10 % to 5%. Prevalence of 20 percent. Based on 95% CI with a allowable error of
10%, sample size was calculated using the formula.

sample size is 4PQ/D2

P= PREVALENCE
Q=1-P
D= PRECISION OF ERROR
4x20x80/100= 64

Based on 95% CI with a allowable error of 5%, sample size was calculated using the
formula
SAMPLE SIZE ==4X20X(100-20)/5 2
4X20X80/25= 256
So as to achieve a 95% CI , with a allowable error between 5% and 10% and with a
estimated prevalence of 20 %, it is decided to keep a sample size of 150 diabetic patients
for the current study.

STUDY DURATION: December 2015-Decembe 2016

INCLUSION CRITERIA:
1) All patients with Type 2 diabetes.
2) All diabetics irrespective of glucose control.
3) All diabetics irrespective of treatment (OHA/insulin).
EXCLUSION CRITERIA:
.1) Type 1 DM
2) Patients with:
a) Gestational diabetes mellitus.
b) Fibrocalculouspancreatitis.
c) Pancreatitis.
d) Steroid induced Diabetes, would be excluded.
3) Adults who are not willing to participate in the study.
4) Known case of Thyroid illness.

STUDY VARIABLES

A. History and Clinical examination, which includes:

1. Duration in years & Symptoms.

2. Goiter

B. Biochemical parameters:

1. FBS, PPBS

2. HbA1c – assess long-term glycemic status

3. Thyroide function (T3, T4 & TSH)

ETHICAL CONSIDERATION

The study commenced after approval from Institutional Ethics

Committee as per IEC No: 19/190/2015/. Subjects who were willing to participate in the
study were enrolled in the study after explaining the study procedure and details
regarding the study. Written informed consent was obtained from the subjects included
in the study before participation in the study.

STUDY PROCEDURE
After obtaining written informed consent from the study participants, examination
findings, anthropometric details, and values of various parameters in blood of subjects
were recorded in separate case record forms (CRF). The data included MRD No:, age,
gender, weight, height, BMI, duration of illness, the glycemic status i.e.,
FPG,PPG,HbA1C. The diagnosis of diabetes mellitus was based on the American
Diabetic Association criteria for type 2 diabetes mellitus, till the required sample size of
study is obtained. Thyroid is assessed by recording symptoms, complications, screened
for thyroid profile (T3, T4& TSH), and Goiter. The laboratory evaluation of thyroid
functions was done by estimation of serum T3, T4 and TSH levels by chemi-lumiscence
assay method. Two ml of blood was drawn and centrifuged and serum (500microml)
collected from that and incubated with the reagent (separate for T3, T4 and TSH) for
about 1 hour at room temperature. Later the readings were taken from the instrument
COBAS 6000. Diabetic states of the patients were estimated by analysing PPBS/FBS
by glucose oxides where in 1ml of blood was drawn and centrifuged to collect the
serum, 10mu of serum is incubated with 1ml of reagent at room temperature for 15min.
Later the reading taken from the instrument. Hba1c level were estimated by Nycocard
Readerxis (Shield) method. BMI calculated using Quetlets Index, BMI=weight/(height
in metres)²

DATA ANALYSIS

Data was collected in separate case record forms (CRF) and were
entered in free to use statistical software R using which complete statistical analysis was
performed. The comparison of means of nominal variables between groups was done
using independent sample ‘t’ test and the comparison of ordinal variables between the
groups were done using Chi Square test. All values were rounded off to one decimal
point and are expressed as mean ± SE of mean. A p value < 0.05 was considered
statistically significant. Adjusted Odds ratio was calculated using logistic regression for
various parameters which showed significant association with Thyroid dysfunction.
RESULTS

Our prospective observational study enrolled 150 study participants who were
diagnosed as having type 2 diabetes mellitus (T2DM) who were attending outpatient and
inpatient department of Sree Gokulam Medical College and Research Foundation,
Venjaramoodu. The baseline characteristics of the study participants are demonstrated in
table 14. and the gender distribution of study participants is demonstrated in figure 4.

Table 14. Baseline parameters of the study participants

Parameter Mean ± SD
Age (years) 60.1 ± 7.9
Weight (Kg) 63.50 ± 6.3
Height (cms) 164.38 ± 6.9
BMI (Kg/m2) 23.5 ± 2.2
FPG (mg/dL) 183.4 ± 20.4
PPG (mg/dL) 279.6 ± 38.1
HbA1C (%) 7.7 ± 0.8
T3 (ng/ml) 1.34 ± 0.48
T4 (μg/dl) 6.78 ± 1.96
TSH (μU/ml) 3.03 ± 2.35
BMI – Body mass index, FPG – Fasting plasma glucose, PPG – Post prandial
glucose, T3 – triiodotyronine, T4 – tetraiodotyronine, TSH- thyroid stimulating
hormone.
Figure 4. Gender distribution of study participants

Among these 150 study participants, 89 (59.3 %) were females and 61 (40.7%)
were males. The mean age of the study participants was 60.1 ± 7.9 years. The mean
duration of diabetes among the study participants was 13 ± 5.9 years. The mean weight,
height and BMI among study participants were 63.5 ± 6.3 kg, 164.4 ± 6.9 cms and 23.5
± 2.2 kg/m2 respectively. Age groups of study participants are demonstrated in table 15.

Table 15. Age distribution of study participants

Age group (years) n (%)

41-50 17 (11.3)
51-60 63 (42)
61-70 52 (34.7)
Table 16. Anthropometric parameters analyzed based on gender

Parameter Gender N Mean ± SD p value

Female 89 60.3 ± 7.8
Age (years)
Male 61 59.9 ± 8.3 * 0.8
Female 89 164.6 ± 7.2
Height (cms)
Male 61 164.1 ± 6.6 * 0.6
Female 89 64.3 ± 6.3
Weight (Kg)
Male 61 62.3 ± 6.3 * 0.051
Female 89 23.8 ± 2.4
BMI (Kg/m2)
Male 61 23.1 ± 1.8 * 0.07
* indicates no significant difference in the means between group according to
independent sample t test. BMI - Body Mass Index.

Body mass index of the study participants included in the study according to BMI asia-
pacific classification is given in table 17, figure 5.

Table 17. Body mass index of the study participants

Weight class based on BMI n (%)

Normal (18.5-22.9 Kg/m2) 65 (43.3)
Overweight (23-24.9 Kg/m2) 60 (40)
Obese 1 (25-29.9 Kg/m2) 23 (15.3)
Obese 2 (≥ 30 Kg/m2) 2 (1.3)
Figure 5. Body mass index of the study participants

The mean duration of diabetes in our study participants was 13 ± 5.9 years. We
categorized our study participants based on duration of diabetes, which is demonstrated
in table 5. Majority of the study participants were receiving oral antidiabetic agent alone
(n= 77, 51.3%) and fewer number of patients were on treatment with insulin (n=38,
25.3%) or a combination of both (n=35, 23.3%). These are depicted in figure 6. Diabetes
associated macrovascular diseases such as ischemic heart disease (IHD), Cerebro-
vascular accidents (CVA), and hypertension were seen in 51 (34%) study participants,
42 (28%) study participants, 92 (61.3%) study participants respectively. Microvascular
complications such as retinopathy, nephropathy and neuropathy were seen in 12 (8%)
study participants, 10 (6.7%) study participants and 12 (8%) study participants
respectively. The mean duration of diabetes in participants with retinopathy was 14.8 ±
6.8 years and 12.8 ± 5.8 years in participants without retinopathy. The mean duration of
diabetes in participants with neuropathy was 14.4 ± 5.8 years and those without
neuropathy was 12.9 ± 5.9 years. The mean duration of diabetes in participants with
nephropathy was 14.1 ± 7.3 years and in those without nephropathy was 12.9 ± 5.8
years.
Figure 6. Treatment regimens of diabetes mellitus among study participants

Table 18. Duration of type 2 diabetes mellitus among study participants

Duration of diabetes (years) n (%)

0-5 15 (10)
6-10 41 (27.3)
11-15 46 (30.7)
16-20 32 (21.3)
>20 16 (10.7)
Figure 7. Duration of type 2 diabetes mellitus among study participants

The mean duration of diabetes in participants with hypertension was 15.8 ± 5.1
years and in those without hypertension was 8.7 ± 4.1 years. The mean duration of
diabetes in participants with ischemic heart disease was 18.2 ± 4.9 years and in those
without ischemic heart disease was 10.4 ± 4.4 years. The mean duration of diabetes in
participants with cerebrovascular accidents was 13.5 ± 4.9 years and in those without
cerebrovascular accidents was 12.8 ± 6.2 years. There was no significant difference in
the blood glucose parameters between males and females. These results are
demonstrated in table 19.
Table 19. Gender based analysis of blood glucose parameters

Parameter Gender N Mean ± SD p value

Female 89 182.2 ± 19.1
FPG (mg/dL)
Male 61 185.2 ± 22.2 0.4
Female 89 276.8 ± 37.1
PPG (mg/dL)
Male 61 283.7 ± 39.3 0.3
Female 88 7.7 ± 0.9
HbA1C (%)
Male 61 7.8 ± 0.7 0.4
FPG- Fasting Plasma Glucose, PPG- Post prandial glucose. Comparison of means were
done using independent sample t test.

Thyroid involvement was assessed using symptoms of thyroid dysfunction and

based on laboratory values of T3, T4 and TSH. Predominant number of patients had no
symptoms of thyroid dysfunction. Only 5 (3.3%) participants had symptoms of thyroid
dysfunction. Similarly very few study participants had palpable swelling of the thyroid
( n=1, 0.7%) and visible swelling of thyroid gland (n=8, 5.3%). These are shown in table
20 and table 21.

Table 20. Symptoms of thyroid dysfunction in study participants

Symptoms n (%)

No symptoms 145 (96.7)

Symptoms present 5 (3.3)

Table 21. Proportion of study participants with thyroid swelling

Thyroid swelling n (%)

No goiter 141 (94)

Palpable 1 (0.7)

Visible 8 (5.3)

Table 22. Gender based analysis of thyroid function among study participants

Parameter Gender N Mean p value

Female 89 1.28 ± 0.54

T3 (ng/ml)
Male 60 1.43 ± 0.36 0.05

Female 89 6.77 ± 2.31

T4 (μg/dl)
Male 61 6.81 ± 1.31 0.8

Female 89 3.34 ± 2.76

TSH (μU/ml)
Male 61 2.59 ± 1.49 0.05

Comparisons of means were done using independent sample t test, a p value < 0.05 was
considered statistically significant

The mean anthropometric and laboratory parameters of the participants with

thyroid swelling are demonstrated in table 23.
Table 23. Anthropometric and laboratory parameters of study participants with thyroid
swelling (palpable & visible)

Parameter (n =9) Mean ± SD

Age (years) 56.2 ± 8.7

Duration of diabetes (years) 13.2 ± 7.8

Weight (Kg) 68.8 ± 8.9
Height (cms) 158.9 ± 9.3
BMI (Kg/m2) 27.3 ± 3.3

FPG (mg/dL) 176.3 ± 31.4

PPG (mg/dL) 266.1 ± 61.9
HbA1C (%) 8.5 ± 1
T3 (ng/ml) 0.9 ± 0.8

T4 (μg/dl) 6.8 ± 5.1

TSH (μU/ml) 6.9 ± 4.2

BMI- Body Mass Index, FPG- Fasting Plasma glucose, PPG- Post Prandial Glucose

Comparison of anthropometric and laboratory parameters between subjects with

symptoms of thyroid dysfunction and those without symptoms of thyroid dysfunction
was done. Similarly comparison of anthropometric and laboratory parameters between
subjects with and without goiter was also done. The results of those comparisons are
demonstrated in table 24.
Table 24. Comparison of anthropometric and laboratory parameters between participants
without goiter and with goiter

Thyroid
Parameter N Mean p value
swelling
No goiter 141 60.4 ± 7.9
Age (years)
Goiter 9 56.2 ± 8.7 0.1
Duration of diabetes No goiter 141 13.0 ± 5.8
(years) Goiter 9 13.2 ± 7.8 0.9
No goiter 141 63.2 ± 6
Weight (Kg)
Goiter 9 68.8 ± 8.9 * 0.01
No goiter 141 164.7 ± 6.7
Height (cms)
Goiter 9 158.9 ± 9.3 * 0.01
No goiter 141 23.3 ± 1.9
BMI (Kg/m2)
Goiter 9 27.3 ± 3.3 * <0.001
No goiter 141 183.9 ± 19.6
FPG (mg/dL)
Goiter 9 176.3 ± 31.4 0.2
No goiter 141 280.5 ± 36.2
PPG (mg/dL)
Goiter 9 266.1 ± 61.9 0.2
No goiter 141 7.7 ± 0.8
HbA1C (%)
Goiter 8 8.5 ± 1 * 0.006
No goiter 140 1.37 ± 0.4
T3 (ng/ml)
Goiter 9 .87 ± 0.8 * 0.002
No goiter 141 6.79 ± 1.6
T4 (μg/dl)
Goiter 9 6.77 ± 5.1 0.9
No goiter 141 2.78 ± 1.9
TSH (μU/ml)
Goiter 9 6.98 ± 4.2 * <0.001
BMI- Body Mass Index, FPG- Fasting Plasma glucose, PPG- Post Prandial Glucose.

* indicates significant difference between the groups with goiter and without goiter
using independent sample t test.
Thyroid disorders were analyzed based on TSH, T3 and T4 levels. This analysis
revealed majority of the study participants as having normal thyroid function (n=125,
83.3%), 20 participants (13.3%) with overt hypothyroidism, 3 participants (2%) with
subclinical hypothyroidism and 2 participants (1.3%) with overt hyperthyroidism. These
are demonstrated in table 25, figure 8.

Table 25. Thyroid dysfunction among study participants

Thyroid function of study participants n (%)

Normal thyroid function 125 (83.3)

Overt hyperthyroidism 2 (1.3)

Subclinical hypothyroidism 3 (2)

Overt hypothyroidism 20 (13.3)

Figure 8. Thyroid function among study participants

Comparison of mean age, height, weight, BMI, duration of diabetes, fasting

plasma glucose, post prandial glucose and HbA1C was done using one way Analysis of
variance (ANOVA), post hoc Bonneferoni showed significant difference between
groups based on their thyroid function. The results of these are showed in table 26.

Table 26. Comparison of means based on participants thyroid function

 Parameter N Mean ± SD p value

Normal thyroid function 125 60.7 ± 7.8 0.1

Overt hyperthyroidism 2 48.5 ± 6.4 0.4
Age (years) Subclinical 59.7 ±
3 0.2
hypothyroidism 12.9
Overt hypothyroidism 20 58.2 ± 7.8 0.8
Normal thyroid function 125 12.9 ± 5.7 1
Duration of Overt hyperthyroidism 2 7.5 ± 2.1 0.06
diabetes Subclinical
3 16 ± 12.2 0.06
(years) hypothyroidism
Overt hypothyroidism 20 13.8 ± 6.1 0.08
Normal thyroid function 125 63 ± 6 0.5
Overt hyperthyroidism 2 60.5 ± 2.1 0.7
Weight
Subclinical
(Kg) 3 65 ± 11.3 0.3
hypothyroidism
Overt hypothyroidism 20 66.6 ± 7.5 0.7
Normal thyroid function 125 165.8 ± 5.4 0.2
Overt hyperthyroidism 2 163.5 ± 2.1 0.3
Height Subclinical
3 153.3 ± 5.8 < 0.001*
(cms) hypothyroidism
Overt hypothyroidism 20 157.2 ± 10 < 0.001*
Normal thyroid function 125 22.9 ± 1.3 0.4
Overt hyperthyroidism 2 22.5 ± 0.02 0.004 #
BMI
Subclinical
(Kg/m2) 3 27.5 ± 2.6 < 0.001 #
hypothyroidism
Overt hypothyroidism 20 27 ± 2.7 < 0.001 #
187.4 ±
Normal thyroid function 125 0.1
14.3
Overt hyperthyroidism 2 178 ± 4.2 0.08
FPG
Subclinical
(mg/dL) 3 150 ± 26 0.004 $
hypothyroidism
164.4 ±
Overt hypothyroidism 20 <0.001 $
34.6
280.5 ±
Normal thyroid function 125 0.09
36.1
253.5 ±
Overt hyperthyroidism 2 0.06
PPG 65.8
(mg/dL) Subclinical 269.3 ±
3 0.07
hypothyroidism 51.4
278.3 ±
Overt hypothyroidism 20 0.1
47.4
Normal thyroid function 125 7.6 ± 0.7 0.1
Overt hyperthyroidism 2 8.8 ± 0.3 0.4
HbA1C
Subclinical
(%) 3 8.2 ± 1.8 0.5
hypothyroidism
Overt hypothyroidism 19 8.1 ± 1.2 0.5
* indicates significant difference when compared to individuals with normal thyroid
function; # indicates significant difference when compared to individuals with normal
thyroid function & between each other; $ indicates significant difference when
compared to individuals with normal thyroid function; there was no significant
difference in other parameters analyzed. BMI- Body Mass Index, FPG- Fasting Plasma
glucose, PPG- Post Prandial Glucose.
Analysis of categorical variables such as retinopathy, nephropathy, neuropathy,
systemic hypertension, coronary artery disease, cerebro vascular accidents, treatment for
diabetes mellitus, swelling of thyroid gland and symptoms of thyroid dysfunction were
analyzed against thyroid function of the study participants and did not show any
significant association. These are demonstrated below.

Table 27. Association of gender and thyroid disorders of study participants

Thyroid function of participants

Gender Overt Subclinical Overt Total

Normal hyper- hypo- hypo-
thyroidism thyroidism thyroidism

Female 69 2 3 15 89

Male 56 0 0 5 61

Total 125 2 3 20 150

Chi square test estimated a p value of 0.09 indicating no significant association

Figure 9. Demonstrating association of gender and type of thyroid dysfunction

Chi square test estimated a p value of 0.5 indicating no association between type of
thyroid dysfunction and gender.

Table 28. Association of retinopathy and sub type of thyroid function of study
participants

Thyroid function of participants

Normal Overt Subclinical Overt
Retinopathy Total
thyroid hyper- hypo- hypo-
function thyroidism thyroidism thyroidism
No 117 2 3 16 138
Yes 8 0 0 4 12
Total 125 2 3 20 150
Chi square showed a p value of 0.2 showing no significant association between groups
Figure 10. Association of thyroid status of participants and retinopathy

No significant association was observed between thyroid status and retinopathy (p=0.1,
OR – 2.8; 95% CI 0.8 – 10.1)

Figure 11. Association of retinopathy and thyroid dysfunction of study participants

Chi square test estimated no association between retinopathy and thyroid dysfunction (p
= 0.6)
Table 29. Association of neuropathy and sub type of thyroid function of study
participants

Thyroid function of study participants

Subclinical
Neuropathy Overt Overt hypo- Total
Normal hypo-
hyperthyroidism thyroidism
thyroidism
No 117 2 3 16 138
Yes 8 0 0 4 12
Total 125 2 3 20 150
Pearson Chi square test estimated a p value of 0.2 indicating no association between the
parameters
Figure 12. Association of neuropathy and thyroid status of study participants

No significant association was observed between thyroid status and neuropathy

(p=0.1,OR – 2.8, 95% CI 0.8 – 10.1)

Figure 13. Association of neuropathy and thyroid function of study participants

No significant association was observed between neuropathy and thyroid dysfunction (p
= 0.9)

Table 30. Association of nephropathy and sub type of thyroid function of study
participants

Thyroid function in study participants

Subclinical Tot
Nephropathy Overt Overt hypo-
Normal hypo- al
hyperthyroidism thyroidism
thyroidism
No 116 2 3 19 140
Yes 9 0 0 1 10
Total 125 2 3 20 150
Pearson Chi square estimated a p value of 0.9 indicating no significant association

Figure 14. Association of thyroid status of participants and nephropathy

No association was observed (p = 0.6, OR – 0.5, 95% CI 0.1 – 4.4)

Figure 15. Association of nephropathy and thyroid dysfunction of study participants

Chi square test estimated no association between thyroid dysfunction and nephropathy
(p = 0.9)

Table 31.Comparison of mean TSH, HbA1C and duration of diabetes based on weight
class
 Parameter Weight class n Mean ± SD p value
Normal 65 2.3 ± 1.1
Overweight 60 2.4 ± 1.3
TSH (μU/ml)
Obese 1 23 6.3 ± 3.6
Obese 2 2 8.6 ± 0.8 < 0.001*
Normal 65 7.6 ± 0.6
Overweight 60 7.7 ± 0.6
HbA1C (%)
Obese 1 22 8 ± 1.4
Obese 2 2 9.1 ± 1.6 0.02#
Normal 65 13.2 ± 5.2
Duration of
Overweight 60 13 ± 6
diabetes
Obese 1 23 12.6 ± 7.4
(years)
Obese 2 2 13.5 ± 5 0.9

* indicates significant difference between normal weight and obese 1 and obese 2 and
also between overweight and obese 1 and obese 2.
# indicates significant difference between normal and obese 1 and obese 2 and
difference between overweight and obese 2.
Table 32. Association of diabetic treatment with sub type of thyroid function in study
participants
Thyroid function in study participants
Treatment of diabetes Overt Subclinical Overt
Total
mellitus Normal hyper- hypo- hypo-
thyroidism thyroidism thyroidism
Oral anti-diabetic
67 0 1 9 77
agents
Insulin 31 0 0 7 38
Insulin + Oral anti-
27 2 2 4 35
diabetic agents
Total 125 2 3 20 150
Pearson Chi square test estimated a p value of 0.08 indicating no association

Figure 16. Association of diabetic treatment with thyroid disease in study participants
No significant association was observed between thyroid disease and diabetic treatment
(p = 0.1)

Table 33. Association of hypertension with sub type of thyroid function among study
participants

Thyroid function among study participants

Subclinical
Hypertension Overt Overt hypo- Total
Normal hypo-
hyperthyroidism thyroidism
thyroidism
No 45 1 1 11 58
Yes 80 1 2 9 92
Total 125 2 3 20 150
Chi square test estimated a p value of 0.4 indicating no association
Figure 17. Association of hypertension and thyroid status of study participants

There was no significant association between thyroid function and hypertension (p=0.1,
OR – 0.5; 95% CI 0.2 – 1.2)

Figure 18. Association of hypertension with thyroid dysfunction in study participants

No significant association was observed between hypertension and thyroid dysfunction
(p = 0.8)
Table 34. Association of ischemic heart disease and sub type of thyroid function of
study participants

Thyroid function among study participants

Ischemic heart
Overt Subclinical Overt hypo- Total
disease Normal
hyperthyroidism hypothyroidism thyroidism

No 81 2 2 14 99
Yes 44 0 1 6 51
Total 125 2 3 20 150
Pearson Chi square test estimated a p value of 0.7 indicating no significant association
Figure 19. Association between ischemic heart disease and thyroid status of study
participants

No association was observed (p= 0.5, OR – 0.7 95% CI 0.3 – 1.8)

Figure 20. Association of ischemic heart disease and thyroid dysfunction in study
participants
Chi square test estimated no significant association between thyroid dysfunction and
ischemic heart disease (p = 0.7)
Table 35. Association of cerebrovascular accidents and sub type of thyroid function
among study participants
Thyroid function of study participants
Cerebrovascular
Overt hyper- Subclinical Overt Total
accident Normal
thyroidism hypothyroidism hypothyroidism

No 89 1 2 16 108
Yes 36 1 1 4 42
Total 125 2 3 20 150
Pearson Chi square estimated a p value of 0.7 indicating no significant association

Figure 21. Association of cerebrovascular accidents and thyroid status of study

participants
No association was observed (p = 0.6, OR – 0.8; 95% CI 0.3 – 2.1)

Figure 22. Association of cerebrovascular accidents and thyroid dysfunction in study

participants
No association was observed between thyroid dysfunction and cerebrovascular accidents
(p = 0.6)

Table 36. Association of thyroid swelling and sub type of thyroid function among study
participants
 Thyroid function among study participants
Goiter Overt Subclinical Overt Total
Normal
hyperthyroidism hypothyroidism hypothyroidism

No
125 0 1 15 141
goiter
Palpable 0 0 0 1 1
Visible 0 2 2 4 8
Total 125 2 3 20 150
Chi square test estimated significant association (p <0.001)

Figure 23. Association of thyroid swelling and thyroid status of study participants

There was significant association (p < 0.001)

Figure 24. Association of thyroid swelling and thyroid dysfunction among study
participants

No association was observed between thyroid swelling and thyroid dysfunction of study
participants (p = 0.054)
Table 37. Association between symptoms of thyroid dysfunction and sub type of thyroid
status of study participants
Thyroid status of study participants
Symptoms of thyroid Overt Subclinical Overt
Total
dysfunction Normal hyperthyr hypothyroid hypothyroi
oidism ism dism
No symptom 125 0 2 18 145
Symptoms present 0 2 1 2 5
Total 125 2 3 20 150
Chi square test estimated a p value < 0.001 indicating significant association
Figure 25. Association between symptoms of thyroid dysfunction and thyroid disease of
study participants

Significant association was observed between symptoms of thyroid dysfunction and

thyroid disease of participants (p = 0.008)
 Analysis of thyroid function among study participants based on their ADA
glycemic goal was done based on their FPG, PPG and HbA1C. Our observation was a
significantly higher number of patients had overt hypothyroidism (n = 16) compared to
those who attained ADA glycemic goal (n = 4). These observations are demonstrated in
table 38, figure 26. None of the study participants had ADA recommended post prandial
glycemic goal (< 180 mg/dL) hence chi square test could not be performed due to
absence of participants with post prandial glycemic control. Participants who attained
ADA glycemic goal for HbA1C (<7%) was analyzed against the thyroid function, no
significant difference was observed between the groups. These are demonstrated in table
39, Figure 27.

Table 38. Correlation of ADA glycemic goal and sub type of thyroid function among
study participants

Thyroid function among study participants

ADA glycemic goal overt subclinical overt
Total
FPG (80-130 mg/Dl) normal hyperthyro hypothyroidi hypothyroid
idism sm ism
Attained glycemic goal 0 0 1 4 5
Not attained glycemic
125 2 2 16 145
goal
Total 125 2 3 20 150

Chi square test estimated a p value of < 0.001 indicating significant association.
Figure 26. Correlation of ADA glycemic goal and thyroid dysfunction among study
participants

Chi square test did not find significant association (p = 0.7)

Table 39. Correlation of ADA glycemic goal and sub type of thyroid function among
study participants
Thyroid function among study participants
Ada glycemic goal Subclinical Overt
Overt Total
HbA1C (< 7 %) Normal hypothyroid hypothyroidi
hyperthyroidism
ism sm
Attained glycemic
15 0 1 5 21
goal
Not attained
110 2 2 15 129
glycemic goal
Total 125 2 3 20 150

Chi square test estimated a p value of 0.3 indicating no significant association

Figure 27. Correlation of ADA glycemic goal and thyroid dysfunction among study
participants

Chi square test estimated no association (p = 0.7)

DISCUSSION

In our study, 150 Type 2 Diabetes mellitus patients, with no previous history of
thyroid dysfunction were taken from diabetic patients those visited to the department of
medicine Sree Gokulam Medical College during the time period of 2015- 2016.

DEMOGRAPHIC DATA

Among these 150 study participants, 89 (59.3 %) were females and 61 (40.7%) were
males in the present study. This is comparable to previous studies done in Kerala, A
study conducted by Jose et al. 134 in south Kerala report 59% female. Oommen et al 135
in Tamilnadu also reports that Diabetes mellitus is higher among females 57%.
Aswathy et al.136 in Kerala report 51%. Dikshit et al 137. study done in diabetic
patients in Kerala also report more female than male. As per the 2011 census report,
Kerala is the states in India with a female to male ratio greater than 0.99. The ratio for
Kerala is 1.084 that is 1084 females per 1000 males, while the national figure is
about 0.940. This may the reason for the greater percentage of women in the study
group138.

The increasing incidence of hyperglycaemia in pregnancy, which affected more than

16% of women who have given live births worldwide in 2015, the condition remains
massively neglected and undertreated139. This may the reason for the greater percentage
of women with diabetes mellitus. In general, women noticed to have higher sex
hormone-binding globulin (SHBG) levels than men and low SHBG concentrations may
be associated with even higher diabetes risk in women compared with men140

OBJECTIVE DATA

In the present study the mean age of the study participants was 60.1 ± 7.9 years. A
141
study done by Ghorpade et al. in pondichery reported the risk of T2DM is higher
for individuals aged 35–50 years and those aged greater than 50 years compared with
the risk in the younger age group. Ramachandran et al. 142study in India report age
standardised prevalence of diabetes and impaired glucose tolerance were 12.1 % and
14.0 % respectively. Diabetes and pre-diabetes showed increasing trend with age.
Individuals under 40 years of age had a higher prevalence of pre-diabetic than
diabetes. A study conducted by Mayer Davis et al. 143in united states report the
incidences of both type 1 and type 2 diabetes among youths increased significantly in
the 2002–2012 period, particularly among youths. One of the most alarming facts in the
changing tendency in the epidemiology of diabetes all over the world is the shift of onset
to a younger age group. The CURES (The Chennai Urban Rural Epidemiology Study)
provided valuable evidence from India in this regard. It was shown that there was a
temporal shift in the age at diagnosis to a younger group when compared to the NUDS
study (National Urban Diabetes Survey ) completed in 2000.144

In the present study the 43% of the participants BMI is normal (18.5-22.9kg/m²), 40%
were overweight (23-24.9 kg/m²) and 15% were obese (25-29.9 kg/m²). Aswathi et
al.145in there study report 55% of participants with diabetes had BMI ≥ 25 kg/m 2 which
is condolatory to present study. Boffetta et al. 146 in their study in India reports the
participants had BMI more in diabetes groups of the study population, the highest BMI
in participants less than 50 years of age. In the present study the mean age of the study
participants was 60.1 ± 7.9 years.

In the present study, on comparison of mean HbA1c between normal weight and obese
1 and obese 2 and also between overweight and obese 1 and obese 2 indicates significant
difference with p value 0.02. Lee et al. 147 in their study report a positive correlation
similar to the present study. Kahn et al. 148stated that obesity has association with an
increased risk of developing insulin resistance and type 2 diabetes. In overweight
individuals, increased amounts of non-esterified fatty acids, hormones, inflammatory
cytokines, glycerol and other factors that are involved in the development of insulin
resistance is released from adipose tissue. Insulin resistance is associated with
dysfunction of pancreatic islet β-cells, the cells that release insulin, fail to control blood
glucose levels in blood.148 This may be the reason for significance on comparison of
mean HbA1c on weight class in the present study.
The mean duration of diabetes in our study participants was 13 ± 5.9 years. This may be
due to the long duration of follow up and increase in life span. At birth life expectancy
in Kerala is 75 years compared to 64 years in India and 77 years in the US. Female life
expectancy in Kerala higher than male, just as it is noted in the developed world.149

According to Indian census 2011, Kerala ranks first in overall (93.9%) and female
(91.98%) literacy. Better literacy of our study group, especially higher female literacy,
could probably account for the better awareness and follow up in our population.150

Thyroid Dysfunction

Thyroid involvement was assessed using symptoms of thyroid dysfunction and based on
laboratory values of T3, T4 and TSH. Predominant number of patients had no symptoms
of thyroid dysfunction. Only 5 (3.3%) participants had symptoms of thyroid
dysfunction. Similarly very few study participants had palpable swelling of the thyroid
( n=1, 0.7%) and visible swelling of thyroid gland (n=8, 5.3%). indicates significant
difference between the groups with symptoms of thyroid dysfunction and without
symptoms of thyroid dysfunction using independent sample t test. Gaitonde et al. 151 in
their study reported that Clinical symptoms of hypothyroidism are nonspecific and may
be difficult to notice clinically, especially in older persons. As the symptoms of thyroid
disease are nonspecific, often they are associated to other medical and psychiatric
conditions. The signs and symptoms may develop over such a long period of time so
that friends, family, and even personal physicians adapt to the changes and do not
perceive the abnormalities. This conditions will prevent the patient from functioning
normally in a work or family environment and this will eventually come to medical
attention. Both of this conditions are difficult to diagnose in the elderly.152

Thyroid disorders were analysed based on TSH, T3 and T4 levels. This analysis
revealed majority of the study participants as having normal thyroid function (n=125,
83.3%), 20 participants (13.3%) with overt hypothyroidism, 3 participants (2%) with
subclinical hypothyroidism and 2 participants (1.3%) with overt hyperthyroidism.
Papazafiropoulou et al.153 in their study report that the overall 12.3% of participants had
thyroid disorder. Perros et al.104 in their study reported that the overall 13.4% of the
participants had thyroid disease. Demitrost and Ranabir in their study reports that
thyroid dysfunction in type 2 DM in Indian participants is higher on comparison with
other studies done in other parts of the world except in one study done in Spain by
Diez et al.130,154 Diabetic patients have a higher chance of thyroid disorders compared to
the normal population, this may be due to fact that with one organ specific disease are
at risk of developing other disorders.94

In present study thyroid dysfunction were more in female as compared to male

that is 20 in 25 participants with thyroid disease were female. Smithson et al. 155, Gray et
al.156,Celani et al.157 in their study observations are consistent with the present study.
This finding is may be due to increased number of weight gains recorded in female
diabetic patients. The Insulin, which is used in treatment of diabetes mellitus
produced in normal quantities or in excess, has been noticed with increased anabolic
activity.

The mean duration of diabetes in Overt hyperthyroidism is 7.5 ± 2.1SD,

Subclinical hypothyroidism is 16 ± 12.2 SD, Overt hypothyroidism is 13.8 ± 6.1SD. Our
results are in concordance with study done by Diez et al. 130, Telwani et al.158 who also
found no significant relationship between presence of thyroid dysfunction and duration
of diabetes. Disorder in genetic expression of a group of genes along with
physiological deviation that leads to impaired glucose utilization and disposition in
muscles, overproduction of hepatic glucose output, and enhanced absorption of
splanchnic glucose. These factors contribute to insulin resistance. Insulin resistance is
also associated with thyroid dysfunction.159

In the present study , comparison of mean TSH between normal weight and
obese 1 and obese 2 and also between overweight and obese 1 and obese 2 showed
significant difference with p value less than 0.001. Solanki et al.160and Verma et
al.161 report a significant relationship between mean TSH and BMI which is similar to
our study. Thyroid hormones regulate basal metabolism, thermogenesis and have a
major role in lipid and glucose metabolism, food intake and fat oxidation. 162 This may
be a reason for significance in the present study. The significance between TSH and
BMI may be mediated by leptin produced by adipose tissue. Leptin physiologically
regulates energy homeostasis by stimulating the central nervous system regarding
adipose tissue reserves. This explains the neuroendocrine and behaviour responses to
overfeeding, thereby regulating food intake and energy utilisation. 163 Leptin is a major
neuroendocrine regulator in the hypothalamic-pituitary-thyroid axis ,by the regulation of
TRH gene expression in the Para ventricular nucleus of hypothalamus, and TSH will
stimulate leptin production and discharge by human adipose tissue. 164–167

In our study there is no association between micro vascular and macro vascular
diseases and thyroid status of study participants. In contrast, in the studies conducted by
Qi et al.168and Chawala et al.169 report that there is significant association between micro
vascular disease and macro vascular disease and thyroid disease. In Kerala prevalence of
thyroid dysfunction is high so that individual in the study group with thyroid disease is
more in number than the micro vascular and macro vascular diseases. 170 This may be the
reason for no significant association.

Analysis of thyroid function among study participants based on their ADA FPG goal
showed that significantly higher number of patients who had not attained glycemic goal
had overt hypothyroidism compared to those who attained ADA glycemic goal. Chi
square test estimation gives a p value of < 0.001 indicating significant association. Cho
et al.171 stated altered thyroid hormones have been described in patients with diabetes
especially those with poor glycemic control. In diabetic patients, the nocturnal TSH
peak is blunted or abolished, and the TSH response to TRH is impaired. Reduced T3
levels have been observed in uncontrolled diabetic patients. This “low T3 state” could
be explained by an impairment in peripheral conversion of T4 to T3 that normalizes
with improvement in glycemic control.4,172,173

Conclusion
Our study concluded that the prevalence of thyroid dysfunction in Type 2 diabetes
patients was 16.7%, females were affected more than males. Hypothyroidism (15.33%)
was observed to be more common than hyperthyroidism (1.33%). Analysis of thyroid
function among study participants based on their ADA FPG goal showed that
significantly higher number of patients who had not attained glycemic goal had overt
hypothyroidism compared to those who attained ADA glycemic goal. Failure to
recognise the presence of abnormal thyroid hormone level in diabetes may be a cause
for poor diabetic control. We recommend all Type 2 Diabetes Mellitus patients should
have baseline evaluation of Thyroid function.

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LIST OF ABBREVIATIONS

BMI Body Mass Index.

BP Blood pressure
CP Case Proforma
CVD Cardiovascular disease.
DBP Diastolic blood pressure
FBS Fasting blood glucose
FPG Fasting plasma glucose
FFA Free Fatty acids.
T3 Triiodothyronine.
T4 Thyroxine.
GAD Glutamic Acid Decarboxylase.
GLUT-2 Glucose Transporter type 2.
GLUT-4 Glucose Transporter type 4.
HbA1C Glycated haemoglobin
HDL-C High density lipoprotein-cholesterol
HR Heart rate
IHD Ischemic heart disease
HTN Hypertension.
IR Insulin Resistance..
rT3 Reverse Triiodothyronine.
SBP Systolic blood pressure
TSH Thyroid Stimulating Hormone.
TRH Thyroid Releasing Hormone.
T2DM Type 2 Diabetes Mellitus
USA United States America.
WHO World Health Organisation.

IPD In patient Department

LDL-C Low-density lipoprotein-cholesterol
MI Myocardial infarction
NPR Non proliferative retinopathy
OPD Out Patient Department
OGTT Oral Glucose Tolerance test
OHA Oral Hpoglycemic Agents
PPBS Post pranidial blood glucose