Hypothyroidism Among the Patients with Type 2 Diabetes Mellitus – Management Considerations of the Two Conditions

Introduction

Hypothyroidism and Type 2 Diabetes Mellitus (T2DM) are disorders of the endocrine system, which is usually seen in routine practice, often tend to co-occur in patients.¹ According to the International Diabetes Federation (IDF) 2017, approximately 425 million adults worldwide have diabetes, in other words as the National Health and Nutrition Examination Survey (NHANES III) has mentioned, approximately 14% of adults suffer from either DM or an impaired fasting glucose level. Studies showed higher incidence of abnormal thyroid hormone levels (46.5%) among diabetic patients; as a comparison, the prevalence of hypothyroidism was higher in women than in men. Overt hypothyroidism (OH) or subclinical hypothyroidism (SH) varies between 2–4% and 4–20%, respectively, and higher in women above the age of 60 years.² A high prevalence of thyroid dysfunction is seen among both types of DM and they require life-long treatment and carry higher risk for cardiovascular disease. In the peripheral tissues, T2 DM reduces the TSH levels and impairs the conversion of thyroxine (T4) to triiodothyronine (T3) which are linked to insulin resistance. ^3-6

Various organs are under the influence of the thyroid hormones especially related to glucose metabolism. Thyroid hormones improve gastrointestinal motility and increase glucose absorption. In the liver, gluconeogenesis is increased due to the activation of phosphoenolpyruvate carboxykinase (PEPCK). Thus, gluconeogenesis occurs through the direct thyroid hormone effect or indirectly through glucagon or catecholamines. Peripheral insulin resistance is caused by enhanced glycogenolysis and hyperinsulinemia with glucose intolerance. This increases the risk of diabetic complications. Lipolysis is increased by thyroid hormone and enhanced serum-free fatty acid levels cause insulin resistance.¹

Clinical guidelines governing the role of detection of thyroid detection in T2DM patients:

The role of diagnosis of thyroid disorders in patients of T2DM have been focussed by several studies. According to these studies, annually lab test for thyroid dysfunction in T2DM patients is required.⁷ Table 1 shows the guidelines for screening thyroid in diabetes patients in the UK and USA. American Thyroid Association guidelines highlight the need for thyroid testing for T2DM patients. These guidelines recommend testing in adults from 35 years of age, and every 5 years. In patients with thyroid disorder (especially goiter or other autoimmune disease) with T2DM, thyroid palpation and TSH testing for diagnosis has been recommended by The American Association of Clinical Endocrinologists, Thyroid Disease Clinical Practice Guidelines (2002). Frequent screening for thyroid disorders can lead to early treatment of subclinical thyroid abnormalities. Assay of TSH is advised at least every 5 years in T2DM patients^[8].

Methodology

A thorough literature search was conducted in Pubmed and Elseiver database to identify relevant original research articles according the research question related to hypothyroidism and type 2 diabetes mellitus. Search terms used were ‘Hypothyroidism OR type 2 diabetes mellitus OR thyroid hormones OR insulin resistence in thyroid dysfunction’. Article search was initiated from June 2020. Letters to editor and data presented at conferences were excluded. Once the data was extracted, relevant studies were selected.

Pathophysiology of Hypothyroidism

Thyroid hormones are essential to control metabolism, growth and other functions. Thyroid hormones are regulated by hypothalamus, which releases TRH (Thyrotrophin releasing hormone) to anterior pituitary gland through hypothalamic-hypophyseal portal system. TRH then stimulates thyrotrophin cells and releases TSH. TRH is a tropic hormone as well as non-trophic hormone. TRH binds to TRH receptors and activates a cascade mediated by G protein coupled receptors. These secondary messengers mobilize intracellular calcium stores and activate protein kinase C and thereby transcription of TSH, fulfilling the trophic role. TRH also acts a non-trophic hormone as it directly stimulates lactotroph cells and releases prolactin, which is responsible for breast tissue growth and lactation. Steps involved in thyroid synthesis are described in Fig.1.⁹

In primary hypothyroidism, decline in thyroid hormone production causes a compensatory elevation in TSH levels. Secondary hypothyroidism is caused by reduction in TSH release and T3, T4 levels. Tertiary hypothyroidism usually occurs in hypothalamic disorders with decrease in TRH, TSH and T3/T4 levels.⁹

Thyroid hormones directly control insulin secretion. In hypothyroidism, reduction in glucose-induced insulin secretion by beta cells causes perturbed expression of GLUT-2 translocation leading to insulin resistance.

Effect of thyroid hormones in metabolism

Constellation of genes associated with physiological variation results in impaired glucose utilization and disposal in muscles, overproduction of hepatic glucose, and increased absorption of splanchnic glucose. These factors contribute to insulin resistance. Due to defects in islet cell function and beta cell mass, T2DM can cause inappropriate release and reduction in insulin storage. Altered insulin secretion leads to various metabolic disorders in T2DM, including hyperglycemia due to defective insulin-stimulated glucose uptake and upregulated production of hepatic glucose.

Hallmarks of hypothyroidism include reduced glucose absorption from GI tract along with peripheral glucose accumulation, gluconeogenesis, reduced glucose disposal and low hepatic glucose output. In subclinical hypothyroidism, the low T3 affects the glucose uptake involving insulin and glucose transporter GLUT4; change in thyroid hormones can increase basal and insulin stimulated glucose transporter system in tissue level. Changes in thyroid hormone levels can also disturb the fat metabolism causing dyslipidaemia due to impaired homeostasis of fatty acids, triglycerides and lipoproteins.¹⁰

Drugs affecting thyroid function

Certain drugs can cause decline in thyroid function leading to hypothyroidism. Primarily drugs used in the treatment of hyperthyroidism can cause hypothyroidism. Other medications that cause hypothyroidism include amiodarone, sulphonylureas, thalidomide, sodium nitroprusside, perchlorates, lithium, interleukins and interferon- alpha therapy. Hypothyroidism may be the result of inhibition of synthesis, release of thyroid hormones and other immune mechanisms related to interferons; certain drugs like tyrosine kinase inhibitors can induce thyroiditis as also drugs that block the receptors of vascular endothelial growth factor¹¹.

Outcome of drug effects on glycaemic control and thyroid function

Patients with coexisting T2DM and TD are on a combination of drugs; they have the potential to alter thyroid function or glycaemic control and hence, alteration in treatment regimen or adjustments in dose of drugs may be required (Table 2).¹²

T2DM type 2 diabetes mellitus, TSH thyroid-stimulating hormone, TD thyroid disorder, IGF1 insulin-like growth factor-1, FT4 free thyroxine

Effects of metformin on thyroid function

Metformin is considered the most widely used antidiabetic drug. Studies have shown that metformin therapy has an important role in decreasing of serum TSH level in patients with hypothyroidism and opposite result in withdrawing of metformin therapy.^13-16

Studies (Distiller et al. 2014) have revealed the decreased level of TSH in hypothyroidism patients with metformin therapy but also showed that metformin monotherapy meaningfully reduce the prevalence of hypothyroidism.¹⁴

Metformin suppresses TSH level by central mechanism as it can cross blood brain barrier. It has inhibitory action of the adenosine-5′-monophosphate-activated kinase (AMPK) in the hypothalamus (contrary action in peripheral tissues such as liver, by suppression of gluconeogenesis via activation of AMPK).^2,13,17

There are several studies related to the thyroid hormone activity and the effect of metformin in patients with T2DM and hypothyroidism. These studies showed a reduction in TSH level in euthyroid patients on levothyroxine (L-T4) as compared to hypothyroid patients who did not receive L-T4 treatment.^2,18,19

Metformin Decreases Thyroid Volume and Nodule Size

Several studies revealed that patients with T2DM had a significantly enlarged thyroid volume and a higher prevalence of thyroid nodules. In addition, metformin therapy in diabetic patients showed smaller thyroid volume and a lower risk for the formation of thyroid nodules in comparison with patients without metformin therapy.^2,13,14,20

Thiazolidinediones (TZD) and Thyroidassociated orbitopathy

Thyroid-associated orbitopathy (TAO), frequently termed as Graves ophthalmopathy, is part of an autoimmune process that can affect the orbital and periorbital tissue and the thyroid gland which includes the expansion of the volume of orbital contents (fat and connective tissues as well as ocular muscles). Peroxisome proliferatoractivated receptor (PPAR)-gamma is an important factor in adipocyte differentiation which is expressed in orbital adipose and connective tissues. Studies have showed enhancement of expression PPAR-gamma in active stages of thyroid-associated orbitopathy. TZDs, PPARgamma agonists (Pioglitazone), when administered to patients with thyroid-associated orbitopathy were associated with aggravation of the ophthalmopathy (increased eye protrusion, a condition often seen in Graves’ disease).^{13,21,22,23,24}

GlucagonLike Peptide1 (GLP1) receptor agonist and thyroid cancer

GLP-1 receptor agonists not only reduces blood glucose as an anti-diabetic therapy but also have significant effects on the thyroid gland, due to the existence of GLP1 receptors. One of the rare types of thyroid cancers is medullary carcinoma, which is derived from thyroid follicular cells and also from thyroid C-cells which secretes calcitonin. Nowadays, GLP-1 receptor agonists have been contraindicated in patients with medullary thyroid cancer and patients with multiple endocrine neoplasia (MEN) type 2, as studies on rodents showed calcitonin release and C-cell proliferation.^13,17,24

Methimazole and insulin autoimmune syndrome

One of the widely used anti-thyroid medications in the treatment of Graves’ disease is Methimazole. The use of methimazole in patients with diabetes mellitus and Graves’ disease is accompanied by the development of insulin autoimmune syndrome as it contains the sulfhydryl group.^13,25

Effects of insulin in thyroid hormones

When insulin and phenylthiourea were compared, the levels of FT4 increased whereas the level of T3 decreased with insulin. On the other hand, after phenylthiourea, the levels of FT4 and T4 decreased while levels of TSH increased.⁴

Conclusion

Based on the several studies, the close association between hypothyroidism and T2DM has been high lighted in this article. In most of the clinical settings, hypothyroidism and T2DM were interdependent. Hypothyroidism is a precipitating factor for hypoglycemia in diabetic patients and thyroid hormones also alter fat and carbohydrate metabolism. Recent findings have evidenced that there exists a complex relationship between subclinical hypothyroidism and that DM can contribute to major cardiovascular complications as a result of impaired lipid metabolism. As untreated or inadequately treated hypothyroid conditions will have an adverse impact on glycemic control, in patients with hypothyroidism and type 2 diabetes mellitus, adequate work up for detection of thyroid disease followed by annual screening along with proper treatment and medication adherence is necessary for good glycemic control and prevention of cardiovascular complications associated with hypothyroidism and type 2 diabetes mellitus.

Conflict of Interest

None.