Biochemistry Review Article

International Journal of Clinical And Diagnostic Research

Volume 1, Issue 1, Nov-Dec 2013.
Glorigin Lifesciences Private Limited.

THYROID DYSFUNCTION IN TYPE 2 DIABETES MELLITUS

Wilma Delphine Silvia CR1, Gandham Rajeev2, Venkata Bharat Kumar Pinnelli3

Abstract
Diabetes Mellitus and thyroid disorders are two main endocrine disorders interrelated to
each other and encountered in clinical practice. Diabetes patients have a higher prevalence of
thyroid disorders than the normal population. Thyroid disease is found in both types 1 and 2
diabetes. A variety of thyroid abnormalities may co-exist and interact with diabetes mellitus.
Diabetes mellitus appears to influence thyroid function in atleast two sites, one at the level of
hypothalamic control of thyroid stimulating hormone (TSH) release and the other at the
conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) in the peripheral tissue. Alterations in
thyroid hormones indicate the characteristics of low T3 syndrome. Marked hyperglycemia
decreases the activity and concentration of hepatic T4 -5' deiodinase. The relationship between
diabetes mellitus and thyroid disorders is characterized by a complex interdependent interaction.
Furthermore, it seems that unidentified thyroid dysfunction could negatively impact diabetes and
its complications. Therefore, management of thyroid dysfunction in patients with diabetes may
prove beneficial.

Author Affiliations: 1Dr. Wilma Delphine Silvia CR, 2Gandham Rajeev, 3Venkata Bharat Kumar
Pinnelli 1,2Department of Biochemistry, Akash Institute of Medical Sciences & Research Centre,
Devanahalli, Bangalore Rural. 3Department of Biochemistry, Vydehi Institute of Medical Sciences
& Research Centre, Bangalore.

Keywords: Diabetes Mellitus, Thyroid Dysfunction, Hypothyroidism, Hyperthyroidism

* Corresponding Author: Dr. Wilma Delphine Silvia CR, MD, DNB, MNAMS, Professor and
Head Department of Biochemistry, Akash Institute of Medical Sciences and Research Centre,
Devanahalli, Bangalore Rural -562110, Karnataka, India. E-mail:widel2008@rediffmail.com,
Contact No: 09448169967, Fax no: +91 80 27681557.

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Wilma D. Silvia, et al., Thyroid Dysfunction in Type 2 Diabetes Mellitus

1. INTRODUCTION
Diabetes Mellitus and thyroid cellular metabolism and thus excess or deficit
disorders are two main endocrine disorders of either of these hormones could result in
[6]
interrelated to each other and encountered in the functional derangement of the other .
clinical practice. Their correlation is poorly The term thyroid diabetes was coined in the
understood and associated with vascular early literature to depict the influence of
complications and responsible for high thyroid hormone alterations in the
[1]
mortality and morbidity . The association deterioration of glucose control [7].
between diabetes and thyroid dysfunction had A variety of thyroid abnormalities
been recognized since 1979 and emphasized may co-exist and interact with diabetes
the importance of screening of diabetic mellitus. The reported frequency of
[2,3]
patients to identify thyroid diseases . hyperthyroidism and hypothyroidism in
Since then a number of the studies have patients with diabetes has varied from 3.2 %
reported the prevalence of thyroid to 4.6 % and 0.7 % to 4.0 % respectively.
dysfunction among diabetes patients to be Diabetes mellitus appears to influence
[4]
between 2.2 to 17% . However, few studies thyroid function in at least two sites, one at
have observed very high prevalence of the level of hypothalamic control of thyroid
thyroid dysfunction in diabetes i.e. 31 % and stimulating hormone (TSH) release and the
46.5% respectively [5]. other at the conversion of thyroxine (T4) to
Diabetes patients have a higher 3,5,3'-triiodothyronine (T3) in the peripheral
prevalence of thyroid disorders than the tissue. Alterations in thyroid hormones
normal population. Thyroid disease is found indicate the characteristics of low T3
in both types 1 and 2 diabetes. Autoimmune syndrome. Marked hyperglycemia decreases
disease associated thyroid dysfunction is the activity and concentration of hepatic T4 -
commonly seen in type 1 diabetes. Type 2 5' deiodinase. The characteristic findings
diabetes is a metabolic disorder caused by include low serum concentrations of T3,
insulin resistance, occurs primarily within the elevated levels of reverse T3 (rT3) and low,
muscles, liver, and fat tissue. Since thyroid normal, or high levels of T4. The values
hormone regulate carbohydrate, lipid, and return to normal after correction of
protein metabolism, with insulin and thyroid hyperglycemia [8].
hormones being intimately involved in

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Wilma D. Silvia, et al., Thyroid Dysfunction in Type 2 Diabetes Mellitus

Thyroid regulation of glucose Besides all of the above described

Homeostasis: mechanisms, thyroid hormones can indirectly
Common pathological mechanisms affect glucose metabolism through
between diabetes and thyroid dysfunction has modulation of energy homeostasis. Although
to be acknowledged that thyroid hormones the underlying mechanisms have not yet been
exert profound effects in the regulation of clearly defined, thyroid hormones have been
glucose homeostasis. These effects include shown to alter the expression of uncoupling
modifications of the circulating levels of proteins in brown adipose tissue involved in
insulin and counter regulatory hormones, effective thermoregulation.
intestinal absorption, hepatic production and More recently, a role for thyroid
the peripheral tissues uptake (fat and muscle) hormones and TRH in the central regulatory
of glucose [8]. pathways for thermogenesis has been
While thyroid hormones stimulate identified. TRH neurons in the hypothalamus
hepatic gluconeogenesis, they also stimulate express both thyroid hormone nuclear
insulin-mediated glucose disposal in skeletal receptors (TRs) and type 4 melanocortin
muscle and adipose tissue. Stimulation of receptor (MC4R), a key receptor involved in
hepatic glucose production by thyroid central energy regulation. Activation of
hormones may be a direct effect on liver gene MC4R reduces food intake and increases
transcription or an indirect effect, acting via a energy expenditure and inactivating
sympathetic pathway from the hypothalamus. mutations in MC4R are associated with
Central interactions of thyroid hormones on obesity. The repressive effect of T3 on the
glucose and lipid regulation also include 5' expression of MC4R helps in conserving
adenosine monophosphate-activated protein energy in hyperthyroid states. Furthermore,
kinase (AMPK), the master-switch of energy both the POMC (pro) and AgRP (Agouti-
homeostasis, as a central target. The related protein) neurons of the arcuate
modulation of insulin sensitivity as well as nucleus act at the MC4R. Thus, T3, by
the feedback of thyroid hormones on appetite reducing the expression of MC4R, has been
and energy expenditure have recently been shown to decrease the hypothalamic
extensively reviewed [8,9]. sensitivity of the POMC and AgRP signaling
[9]
.

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Wilma D. Silvia, et al., Thyroid Dysfunction in Type 2 Diabetes Mellitus

Effects of thyroid hormones at hepatic

tissue: synthesis explaining the antagonistic insulin
Several genes involved in effect of thyroid hormones at the liver. An
gluconeogenesis, glycogen metabolism and induction of 2-adrenergic receptor mRNA
insulin signaling that are regulated by thyroid and repression of inhibitory G protein (Gi)
hormones in the liver have been identified. RNA of the adenylate cyclase cascade by
Importantly, pyruvate carboxylase the thyroid hormones were also reported. By this
gluconeogenic enzyme involved in the mechanism, thyroid hormones would
formation of oxaloacetate through facilitate the glycogenolytic and
carboxylation of pyruvate in the gluconeogenic effects of epinephrine and
mitochondria and phosphoenolpyruvate glucagon. An increased hepatic expression of
carboxykinase (PEPCK), the enzyme that the glucose transporter GLUT2 the principal
catalyzes the rate-controlling step of transporter for transfer of glucose between
gluconeogenesis by decarboxylation and liver and blood is also part of the insulin
phosphorylation of oxaloacetate to produce antagonistic effects of thyroid hormones at
phosphoenolpyruvate, are a target of T3. the liver that lead to an increased glucose
[11]
Moreover, an increase in glucose-6- hepatic output . Most recently, a neural
phosphatase mRNA expression, the enzyme (autonomic) modulation of hepatic glucose
that hydrolyzes glucose-6phosphate and metabolism by T3 at the hypothalamus that
completes the final step in gluconeogenesis takes place independently of plasma gluco-
and glycogenolysis, with T3 has been regulatory hormone concentrations has been
described [8,10]. described. It was shown that upon selective
A thyroid hormone mediated decrease administration to the paraventricular nucleus
in Akt2 (protein kinase B) mRNA (PVN), T3 increases endogenous glucose
expression, a serine/threonine kinase that is production and plasma glucose, and these
key in the insulin signaling pathway has also hypothalamic T3 effects are mediated via
been reported. Akt2 participates in liver sympathetic projections to the liver. This
glycogen synthesis by inactivating glycogen response is independent of plasma T3,
synthase kinase 3, in charge of inactivating insulin, and corticosterone concentrations.
glycogen synthase. Thus, a decrease in Akt2
activity would in turn, decrease glycogen

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Wilma D. Silvia, et al.,
Effects of thyroid hormones at the
peripheral tissue:
At peripheral tissues, thyroid
hormones also regulate the expression of
genes that affect glucose transport and
glycolysis respectively. However, contrary to
what happens at the liver level, some of these
effects are synergistic with insulin. In skeletal
muscle, the main site of insulin-mediated
glucose disposal, glucose transporter GLUT4
is induced by thyroid hormone, revealing that
T3 can increase basal and insulin-stimulated
glucose transport in this tissue. It has also
been reported that in skin fibroblasts the
mRNA of the transcription Hypoxia-
inducible factor 1 (HIF-1), a key mediator of
glycolysis, increases in response to T3.
Another target of thyroid hormones is
peroxisome proliferator- activated receptor
gamma coactivator 1-alpha (PGC-1 alpha),
an essential transcriptional regulator of
mitochondrial content and function, fatty acid
oxidation, and gluconeogenesis. A decreased
expression of PGC-1 alpha in the presence of
diminished thyroid hormones can determine
cellular lipid excess and impaired oxidative
metabolism, characteristic of type 2 diabetes.
Apart from the serum levels of T3,
the hormonal message is modulated by its
intracellular concentration, dependent upon
the activity of deiodinases. A lower
Intl. J Clin. Diag. Res. 2014;1(1):IV
Thyroid Dysfunction in Type 2 Diabetes Mellitus
expression and activity of type 2
iodothyronine-deiodinase (D2), has been
found to be associated with insulin resistance
[8,12]
.
Effect of Diabetes on Thyroid Function:
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
impairment in peripheral conversion of T4 to
T3 that normalizes with improvement in
glycemic control. Higher levels of circulating
insulin associated with insulin resistance
have shown a proliferative effect on thyroid
tissue resulting in larger thyroid size with
increased formation of nodules.
Type2 Diabetes & Hypothyroidism:
The diabetics showed trend towards
hypothyroidism. The pathophysiology of
thyroid dysfunction in diabetes is still
unclear; however thyroid antibodies have
been suggested to be the causative factors.
Hypothyroidism & subclinical
hypothyroidism are frequent co-morbidities
in patients with DM, a TSH level determined
at diagnosis of diabetes may predict
hypothyroidism even at concentrations within
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Wilma D. Silvia, et al., Thyroid Dysfunction in Type 2 Diabetes Mellitus

[13]
the reference range . Hypothyroidism is Type2 Diabetes & Hyperthyroidism:
characterized by impaired glucose absorption Thyroid hormones affect glucose
from gastrointestinal tract and delayed metabolism via several mechanisms.
peripheral glucose assimilation and Hyperthyroidism has long been recognized to
gluconeogenesis, decreased or normal hepatic promote hyperglycemia. During
glucose output and decreased peripheral hyperthyroidism, the half-life of insulin is
tissue glucose disposal. Moreover, while in reduced most likely secondary to an
hypothyroidism the inability of insulin to increased rate of degradation and an
sufficiently sustain glucose utilization by the enhanced release of biologically inactive
muscles leads to insulin resistance. insulin precursors. Hyperthyroidism was
Subclinical hypothyroidism may also associated with a reduced C-peptide to
constitute an insulin resistance state. Glucose proinsulin ratio suggesting an underlying
disposal is decreased in hypothyroidism, defect in proinsulin processing. Another
while glucose-stimulated insulin secretion is mechanism explaining the relationship
increased, presumably because of insulin between hyperthyroidism and hyperglycemia
[13]
resistance . Patients with subclinical is the increase in glucose gut absorption
hypothyroidism sustain an obvious increase mediated by the excess thyroid hormones.
in cardiovascular event rates. Despite this, Endogenous production of glucose is also
there is a distinct lack of relevant research enhanced in hyperthyroidism via several
into risk factors associated with mechanisms.
microvascular complications in type 2 Thyroid hormones produce an
diabetes with subclinical hypothyroidism. increase in the hepatocyte plasma membrane
Several studies focused predominantly on the concentrations of GLUT2 which is the main
issue of diabetic nephropathy, as defined glucose transporter in the liver, and
solely by elevated microalbuminuria, rather consequently, the increased levels of GLUT-
than retinopathy. However, in most diabetic 2 contribute to the increased hepatic glucose
patients with elevated microalbuminuria, output and abnormal glucose metabolism.
other chronic kidney diseases should be Additionally, increased lipolysis is observed
considered in the absence of diabetic in hyperthyroidism resulting in an increase in
retinopathy [14]. free fatty acids that stimulates hepatic
gluconeogenesis. The increased release of

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Wilma D. Silvia, et al., Thyroid Dysfunction in Type 2 Diabetes Mellitus

free fatty acids could partially be explained an increased glucose turnover with increased
by an enhanced catecholamine-stimulated glucose absorption through the
lipolysis induced by the excess thyroid gastrointestinal tract, postabsorptive
hormones. Moreover, the nonoxidative hyperglycaemia and elevated hepatic glucose
glucose disposal in hyperthyroidism is output, along with elevated fasting or
enhanced resulting in an overproduction of postprandial insulin and proinsulin levels,
lactate that enters the Cori cycle and elevated free fatty acid concentrations and
promotes further hepatic gluconeogenesis. elevated peripheral glucose transport and
The increase in growth hormone, glucagon utilization. In peripheral tissues there is a
and catecholamine levels associated with massive arrival of glucose to the cells that
hyperthyroidism further contributes to the overwhelms the Krebs cycle resulting in an
impaired glucose tolerance. It is well known increased metabolism of glucose through the
that diabetic patients with hyperthyroidism nonoxidative pathway. Lactate produced in
experience worsening of their glycemic great quantities in the cells returns to the liver
control and thyrotoxicosis has been shown to and participates in the Cori cycle where four
precipitate diabetic ketoacidosis in subjects ATP molecules are wasted for each glucose
with diabetes [8,15,16]. molecule that is created. Although glucose
Pathological mechanisms common to uptake in peripheral tissues has been
thyroid disorders and diabetes described as either normal or increased
Thyroid hormones act differentially in reduced insulin stimulated peripheral glucose
liver, skeletal muscle and adipose tissue the utilization has also been demonstrated in
main targets of insulin action. Thyroid hyperthyroidism [17].
disorders have a major impact on glucose CONCLUSION:
control. When thyroid dysfunction ensues the The relationship between diabetes
glucose homeostatic balance is broken. mellitus and thyroid disorders is
Insulin resistance, mainly associated with characterized by a complex interdependent
increased hepatic gluconeogenesis, is interaction. Furthermore, it seems that
characteristic of an excess of thyroid unidentified thyroid dysfunction could
hormones and explains why glucose control negatively impact diabetes and its
deteriorates when diabetic patients develop complications. A higher frequency of cardio
hyperthyroidism. Thyrotoxic patients show vascular events, retinopathy and nephropathy

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Wilma D. Silvia, et al., Thyroid Dysfunction in Type 2 Diabetes Mellitus

was observed in diabetic patients with Trop Med Public Health. 2008;
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patients with diabetes may prove beneficial. Akaln, et al. Thyroid Disease in
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