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:[email protected], Contact No: 09448169967, Fax no: +91 80 27681557.

Intl. J Clin. Diag. Res. 2014;1(1):IV

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Wilma D. Silvia, et al.,

Thyroid Dysfunction in Type 2 Diabetes Mellitus

1. INTRODUCTION Diabetes

Mellitus

thyroid

cellular metabolism and thus excess or deficit

disorders are two main endocrine disorders

of either of these hormones could result in

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

mortality and morbidity

[1]

and

. The association

hormone

alterations

in

[6]

.

the

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.

patients to identify thyroid diseases

[2,3]

.

The

hyperthyroidism

reported and

frequency

of

hypothyroidism

in

Since then a number of the studies have

patients with diabetes has varied from 3.2 %

reported

to 4.6 % and 0.7 % to 4.0 % respectively.

the

prevalence

of

thyroid

dysfunction among diabetes patients to be between 2.2 to 17%

[4]

Diabetes

mellitus

appears

to

influence

. 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

protein metabolism, with insulin and thyroid

hyperglycemia [8].

to

normal

after

correction

hormones being intimately involved in Intl. J Clin. Diag. Res. 2014;1(1):IV

www.ijcdr.net

of

Wilma D. Silvia, et al.,

Thyroid

Thyroid Dysfunction in Type 2 Diabetes Mellitus

regulation

of

Besides all of the above described

glucose

mechanisms, thyroid hormones can indirectly

Homeostasis: 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

While thyroid hormones stimulate

for

thermogenesis

has

been

identified. TRH neurons in the hypothalamus

hepatic gluconeogenesis, they also stimulate

express

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

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

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,

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

extensively reviewed [8,9].

sensitivity of the POMC and AgRP signaling

glucose

as

production

a

central

by

target.

[9]

Intl. J Clin. Diag. Res. 2014;1(1):IV

both

thyroid

expenditure

to

decrease

hormone

and

the

nuclear

inactivating

hypothalamic

.

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Wilma D. Silvia, et al.,

Thyroid Dysfunction in Type 2 Diabetes Mellitus

Effects of thyroid hormones at hepatic synthesis explaining the antagonistic insulin

tissue: Several

genes

in

effect of thyroid hormones at the liver. An

gluconeogenesis, glycogen metabolism and

induction of β2-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,

thyroid hormones were also reported. By this

pyruvate

involved

carboxylase

the

gluconeogenic enzyme involved in the

mechanism,

formation

facilitate

of

oxaloacetate

carboxylation

of

mitochondria

and

through

would

glycogenolytic

and

gluconeogenic effects of epinephrine and

phosphoenolpyruvate

glucagon. An increased hepatic expression of

carboxykinase (PEPCK), the enzyme that

the glucose transporter GLUT2 the principal

catalyzes

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

Moreover,

hepatic output

an

in

the

hormones

the

the

pyruvate

thyroid

rate-controlling

increase

in

step

glucose-6-

[11]

. Most recently, a neural

phosphatase mRNA expression, the enzyme

(autonomic) modulation of hepatic glucose

that hydrolyzes glucose-6–phosphate 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 in

Akt2

(protein

kinase

B)

administration to the paraventricular nucleus

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 Intl. J Clin. Diag. Res. 2014;1(1):IV

www.ijcdr.net

Wilma D. Silvia, et al.,

Effects

of

Thyroid Dysfunction in Type 2 Diabetes Mellitus

thyroid

hormones

at

the

and

activity

of

type

2

iodothyronine-deiodinase (D2), has been

peripheral tissue: At

expression

peripheral

tissues,

thyroid

found to be associated with insulin resistance

hormones also regulate the expression of

[8,12]

genes that affect glucose transport and

Effect of Diabetes on Thyroid Function:

.

glycolysis respectively. However, contrary to

Altered thyroid hormones have been

what happens at the liver level, some of these

described in patients with diabetes especially

effects are synergistic with insulin. In skeletal

those with poor glycemic control. In diabetic

muscle, the main site of insulin-mediated

patients, the nocturnal TSH peak is blunted

glucose disposal, glucose transporter GLUT4

or abolished, and the TSH response to TRH

is induced by thyroid hormone, revealing that

is impaired. Reduced T3 levels have been

T3 can increase basal and insulin-stimulated

observed in uncontrolled diabetic patients.

glucose transport in this tissue. It has also

This “low T3 state” could be explained by

been reported that in skin fibroblasts the

impairment in peripheral conversion of T4 to

mRNA

Hypoxia-

T3 that normalizes with improvement in

inducible factor 1 (HIF-1), a key mediator of

glycemic control. Higher levels of circulating

glycolysis, increases in response to T3.

insulin associated with insulin resistance

Another target of thyroid hormones is

have shown a proliferative effect on thyroid

peroxisome proliferator- activated receptor

tissue resulting in larger thyroid size with

gamma coactivator 1-alpha (PGC-1 alpha),

increased formation of nodules.

an essential transcriptional regulator of

Type2 Diabetes & Hypothyroidism:

of

the

transcription

mitochondrial content and function, fatty acid

The diabetics showed trend towards

oxidation, and gluconeogenesis. A decreased

hypothyroidism. The pathophysiology of

expression of PGC-1 alpha in the presence of

thyroid dysfunction in diabetes is still

diminished thyroid hormones can determine

unclear; however thyroid antibodies have

cellular lipid excess and impaired oxidative

been suggested to be the causative factors.

metabolism, characteristic of type 2 diabetes.

Hypothyroidism

&

subclinical

Apart from the serum levels of T3,

hypothyroidism are frequent co-morbidities

the hormonal message is modulated by its

in patients with DM, a TSH level determined

intracellular concentration, dependent upon

at

the

hypothyroidism even at concentrations within

activity

of

deiodinases.

Intl. J Clin. Diag. Res. 2014;1(1):IV

A

lower

diagnosis

of

diabetes

may

predict

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Wilma D. Silvia, et al.,

Thyroid Dysfunction in Type 2 Diabetes Mellitus

the reference range

[13]

. Hypothyroidism is

characterized by impaired glucose absorption from

gastrointestinal

peripheral

glucose

tract

and delayed

assimilation

and

Type2 Diabetes & Hyperthyroidism: Thyroid hormones affect glucose metabolism

via

several

mechanisms.

Hyperthyroidism has long been recognized to

gluconeogenesis, decreased or normal hepatic

promote

glucose output and decreased peripheral

hyperthyroidism, the half-life of insulin is

tissue glucose disposal. Moreover, while in

reduced

hypothyroidism the inability of insulin to

increased

sufficiently sustain glucose utilization by the

enhanced release of biologically inactive

muscles

insulin precursors. Hyperthyroidism was

leads

Subclinical

to

insulin

rate

likely of

secondary

degradation

to

an

and

an

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

increased, presumably because of insulin

between hyperthyroidism and hyperglycemia

[13]

may

most

During

also

resistance

hypothyroidism

resistance.

hyperglycemia.

explaining

the

relationship

. 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

mechanisms.

risk

microvascular

factors

associated

complications

in

with 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

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

transporter

in

the

liver,

and

gluconeogenesis. The increased release of Intl. J Clin. Diag. Res. 2014;1(1):IV

www.ijcdr.net

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

lipolysis induced by the excess thyroid

gastrointestinal

hormones.

hyperglycaemia and elevated hepatic glucose

Moreover,

glucose disposal

nonoxidative

hyperthyroidism

through

tract,

the

postabsorptive

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

in

the

absorption

mechanisms

common

to

uptake in

peripheral

tissues has

been

described as either normal or increased

thyroid disorders and diabetes 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

Insulin resistance, mainly associated with

characterized by a complex interdependent

increased

interaction.

hepatic

gluconeogenesis,

is

and

thyroid

Furthermore,

it

seems

that

unidentified

hormones and explains why glucose control

negatively

deteriorates when diabetic patients develop

complications. A higher frequency of cardio

hyperthyroidism. Thyrotoxic patients show

vascular events, retinopathy and nephropathy

impact

dysfunction

is

characteristic of an excess of thyroid

Intl. J Clin. Diag. Res. 2014;1(1):IV

thyroid

disorders

diabetes

and

www.ijcdr.net

could its

Wilma D. Silvia, et al.,

Thyroid Dysfunction in Type 2 Diabetes Mellitus

was observed in diabetic patients with

Trop

subclinical

hypothyroidism.

39(5):913-916.

management

of

thyroid

Therefore,

dysfunction

in

7. Engin

Med

Public

G.ney,

Health.

2008;

Efe,

Aysen

Belgin

patients with diabetes may prove beneficial.

AkalÝn, et al. Thyroid Disease in

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