DOI: https://doi.org/10.53350/pjmhs22166828 ORIGINAL ARTICLE 828 P J M H S Vol. 16, No. 06, Jun 2022 Diabetes: Insights into Thyroid Hormones SHAHID SHEHZAD 1 , MUHAMMAD NAEEM 2 , RASIF KHAN 3 , RASHED ALI KHAN 4 , SAQIBAH REHMAN 5 , RIDA NAZ 6 1 Department of Diabetes and Endocrinology, Lady Reading Hospital Peshawar 2 Medical officer DHQ Teaching Hospital Swabi 3 District Medical Specialist Category B hospital Chakdara Dir Lower 4 District Medical Specialist, Civil hospital Madyan Swat 5 Assistant Professor of Pathology, Mphil Chemical Pathology, Gomal Medical College Dera Ismail Khan 6 Regional Blood Centre, Dera Ismail Khan-29050-Pakistan Correspondence to: Dr. Rida Naz, Email: dr.ridaanaz@gmail.com ABSTRACT Numerous physiological and pathological processes must be controlled for the thyroid gland to function properly. Research utilising both animal models and human subjects has demonstrated that thyroid hormones regulate cellular processes that are crucial for most age-related diseases. Furthermore, both hyperthyroidism and hypothyroidism have been associated to the onset of several kinds of diabetes, proving the intricacy of the molecular processes regulated by thyroid hormones. In this article, we provide a summary of the most recent thyroid hormone-related findings in the field of diabetes research. We contend that despite the difficulty in developing thyromimetics due to their inefficiency and potential toxicity, therapies based on the use of modulators of thyroid hormone activity may be therapeutically beneficial in some kinds of diabetes. INTRODUCTION The production of thyroid hormone (TH) is carefully regulated by a negative feedback loop that involves the hypothalamus, the pituitary gland, and the thyroid axis (Figure 1). The hypothalamus is responsible for the production of TRH. After being secreted, TRH causes an increase in the synthesis of TSH by interacting with a receptor for TRH in the pituitary gland (Liu et al., 2019). Within the thyroid, TSH binds to TSHR to stimulate the production of TH by the thyroid. The hormones triiodothyronine (T3) and tetraiodothyronine (T4) are only secreted when they are required. THs are responsible for maintaining constant levels of TRH, TSH, and TH by completing a negative feedback loop that restricts the production and secretion of TRH and TSH via THR in the hypothalamus and pituitary gland. Figure 1: Thyroid Hormone Production and Function Scheme Deiodinases (DIO2 and DIO3) take T4 as their starting material and remove the 5′ iodine to create T3. Regardless of the amounts of circulating TH, the effects of TH are controlled by the production of deiodinase that is cell-type and tissue-specific (Schweizer et al., 2008). Binding of intracellular T3 occurs via the TH receptor (THR) and the THR, both of which have a high affinity for the TH response components (TREs). THRs are known to form a transcription co-activator complex when they bind to their respective ligands (Perissi et al., 2010). THR is known to have interactions with a variety of different nuclear hormone receptors, including peroxisome proliferator-activated receptors, retinoid X receptors, retinoic acid receptors, and liver X receptors. Because of this, binding to a wide variety of nucleotide sequences that regulate different metabolic pathways, such as cholesterol, glucose, and fatty acid metabolism, is made possible (Kouidhi and Clerget-Froidevaux, 2018). PI3 K-AKT-FOXO1 and mTOR-p70S6 K signalling are two examples of protein-protein interactions that are examples of additional ways that THs influence transcription (Flamant et al., 2017). THRs influence more than 80 genes, the majority of which are involved in processes such as de novo lipogenesis, the tricarboxylic acid cycle, oxidative phosphorylation, mitochondrial biogenesis, and the catabolism of fatty acids (Singh et al., 2018). Catabolism of all forms of energy can be attributed to THs due to their ability to increase oxygen consumption, ATP hydrolysis, and mitochondrial coupling (Johannsen et al., 2012). THs have the effect of elevating the basal metabolic rate, often known as the energy expenditure at rest. THs are essential to both the growth of tissues and the maintenance of overall health (Ng et al., 2013). TSH levels can range anywhere from 0.39 to 4.6 mIU/L, whereas total T4 levels can be anywhere from 57.9 to 169.9 nM. (Hollowell et al., 2002). TH changes should fall somewhere in the range of 0.5 percent to 4 percent in regions that receive an acceptable amount of iodine. Clinical hypothyroidism, also known as overt hypothyroidism (Taylor et al., 2013), is linked to metabolic dysregulations that heighten the risk of cardiovascular issues and diabetes mellitus (DM), including hypercholesterolemia and elevated LDL levels. Subclinical hypothyroidism has been linked to poor neurocognitive health, an unbalanced bone metabolism, type 2 diabetes (T2DM), cardiovascular risk factors including high LDL and VLDL levels, hypertriglyceridemia, hypertension, atrial fibrillation, and obesity, as well as low HDL levels and early mortality (Biondi et al., 2019). Patients who have hyperthyroidism have an increased risk of developing diabetes and cardiovascular issues, both of which can lead to mortality at an earlier age (Brandt et al., 2013). Subclinical hyperthyroidism with low TSH levels is associated with an increased risk of neurocognitive impairment and dementia (Aubert et al., 2017). The risk of fracture is elevated in patients with both overt and subclinical hyperthyroidism (Blum et al., 2015). Thyroid hormones in diabetes mellitus Thyroid hormones and glucose/lipid metabolism: The breakdown of accumulated energy occurs because of THs increasing the body's need for oxygen (Johannsen et al., 2012). THs regulate the metabolism of lipids and glucose. THs reduce triglycerides and lipoproteins with high levels of cholesterol. THs boost the expression of Srebp2 (Mullur et al., 2014). Srebp-2 increases the expression of LDL receptors, which causes an increase in hepatic cholesterol uptake. In the body, THs promote both lipolysis and lipogenesis. Both acetyl-coenzyme A carboxylase and carnitine palmitoyl transferase I, which are involved in lipogenesis and mitochondrial fatty acid absorption, are increased by THs (Mullur et al., 2014). An in-depth analysis of these processes reveals that in the context of considerable lipolysis, liponeogenesis must be increased to maintain stable lipid levels (Oppenheimer et al., 1991). In these conditions, lipolysis acts to promote thermogenesis. TH may have an impact on how carbs are metabolised.