Thyroid Hormone and Diabetes Mellitus Interplay: Making Management of Comorbid Disorders Complicated

Keywords

thyroid hormones - insulin resistance - diabetes mellitus - thyroid disorder - hyperglycemia

Introduction

Thyroid hormone is essential for normal development, growth, and calorigenic action. While insulin helps in maintaining normal glucose level in body, hyperthyroidism is a condition characterized by excessive metabolism, resulting in an elevated requirement for glucose, causing insulin resistance in peripheral tissues and can also lead to ketoacidosis. Whereas in diabetes mellitus (DM), thyroid stimulating hormone (TSH) levels become abnormal. Resulting treatment of subclinical hypothyroidism is difficult due to complications like diabetic retinopathy, peripheral arterial disease, diabetic nephropathy, and diabetic peripheral neuropathy. This interplay of both hormones makes treatment difficult as many antidiabetic drugs worsen the thyroid condition and vice versa.

Overview of thyroid hormone action

Thyroid hormone is important for metabolism and growth process. Including facilitating an increase in carbohydrate, fat, and protein metabolism in peripheral tissue, such activities are also brought in conjunction with other hormones such as insulin, glucagon, catecholamines, and glucocorticoids [1]. It promotes growth by directly acting on cells and indirectly influencing the growth hormones production, potentiating its effect on its target tissue; calcitonin released from thyroid gland help in skeletal development [2] and growth of central nervous system [3].

Glucose homeostasis and the role of insulin

A healthy life is linked with the balance of blood glucose levels in the body, as it ensures proper regulation of energy balance, hormonal balance, metabolic activity, brain and other organ function, etc. The increase in plasma concentration of glucose is due to the rate of gastric emptying, glycogenolysis by the liver, and the formation of glucose from non-carbohydrate substrates such as lactate, amino acids, and glycerol (gluconeogenesis) [4]. Glucose present in the plasma is maintained by two main hormones insulin and glucagon. Pancreatic β-cells releases insulin, which reduces the blood glucose levels through three major distinct mechanisms. First, it facilitates the uptake of glucose by peripheral tissues such as skeletal muscle and adipocytes, which are rich in insulin receptors [5] [6]. Second, it promotes the liver to store glucose in the form of glycogen or by converting it into fatty acids [7]. Lastly, it effectively suppresses the secretion of glucagon after a meal [8] ([Fig. 1]).

Fig. 1 Role of insulin in lowering blood glucose level.

Epidemiological statistics on the co-occurrence of TD and T2DM

Based on observational prevalence of thyroid disorder, a comprehensive meta-analysis has estimated that these conditions impact approximately 3.82% of the overall population [9]. While the most prevalent endocrinopathy globally is diabetes mellitus (DM), which is caused due to insulin resistance and/or low levels of insulin secretion, resulting in hyperglycemia. According to the International Diabetes Federation, around 10.5% of the adult population (537 million individuals) were affected by DM in 2021. Projections indicate that this number will increase to 643 million by the year 2030 [IDF diabetes atlas, 2021]. A correlation between both disorders is commonly observed, as the occurrence of TD in T2DM patients is more comparatively to non-glycemic patients, ranging from 9.9% to 48% [10] [11]. This can be diagnosed by the presence of antithyroglobulin antibody (anti-TG), anti-thyroid peroxidase (anti-TPO), or both. Enhanced screening for thyroid disorder (TD) is crucial in patients with type 2 diabetes mellitus (T2DM), as numerous studies have revealed a high prevalence of subclinical hypothyroidism (SCH) among them. Furthermore, clinical evaluations have led to the identification of several new cases of TD in T2DM patients, emphasizing the importance of thorough screening protocols [12].

Prevalence of TD in T2DM patients

Type 2 diabetes mellitus occurs due to a decrease in the secretion of insulin by β cells of the pancreas and often accompanied by insulin resistance [13]. β Cell starts secreting more insulin to cope up with early insulin resistance but due to hyperinsulinemia causes, cells starts getting saturated, and the onset of T2DM is observed in adults [14]. Insulin resistance occurs when there is an increase in glucose uptake and its utilization in peripheral tissues (skeletal muscles, adipose tissue and liver) and cells are less sensitive to insulin binding [15]. Conditions like PCO (polycystic ovarian syndrome), atherosclerosis, and emergence hypertension arise due to metabolic syndrome (MetS) and cardiovascular issues accompanying insulin resistance conditions [16]. Thyroid disorder is more prevalent in patients with type 2 diabetes mellitus compared to the normal population as observed in a study done on the goiter prevalence in normal and diabetic patients [17]. Another study suggests that the likeliness of thyroid disorder in T2DM patients is around 16.2%, with hypothyroidism (14%) being more common compared to hyperthyroidism (2.2%). Females have a higher risk of thyroid disorder compared to males [18]. Furthermore, the clinical features that are observed in diabetic patients suffering from thyroid disorders are shown in ([Fig. 2]).

Fig. 2 Clinical features that are observed in diabetic patients dext-linkng both hypothyroidism and hyperthyroidism.

Diabetes mellitus (DM) affecting thyroid hormones

Diabetes mellitus alters the TSH level due to insulin resistance, causing lower production of triiodothyronine (T3) by reducing the conversion of T3 from tetraiodothyronine (T4). In individuals who have diabetes mellitus (DM) and normal thyroid function, it has been observed that the nocturnal peak of thyroid-stimulating hormone (TSH) is either absent or weak. Additionally, their TSH response to thyrotropin-releasing hormone (TRH) is also compromised [19]. Additionally, certain acute conditions like diabetic ketoacidosis can complicate thyroid function tests by reducing T3 and T4 levels while TSH levels remain unaffected. Changes in thyroid hormones are also observed during medicating in T2DM patients. For instance, insulin therapy causes an increase in free tetraiodothyronine or thyroxine (FT4), but free triiodothyronine (FT3) levels and oral hypoglycemic agents disrupt TSH and TH levels. Both are discussed in the article.

Subclinical hypo and hyperthyroidism and diabetes

Hypothyroidism poses not only a threat of obesity and dyslipidemia but also increases the risk of metabolic syndrome and diabetes mellitus. As previously stated, an excess of thyroid hormone leads to insulin resistance and glucose intolerance. Furthermore, a deficiency of thyroid hormone is also linked to insulin resistance and glucose intolerance. It has been reported that treating hypothyroidism can enhance insulin sensitivity [20]. The complete elucidation of the specific mechanism behind the accelerated impact of subclinical hypothyroidism on diabetic complications remains unclear. Individuals with subclinical hypothyroidism might experience a reduction in cardiac output, renal flow, glomerular filtration, and an elevation in vascular resistance. The increased occurrence of diabetic nephropathy in individuals with subclinical hypothyroidism could potentially be attributed to these alterations. Furthermore, thyroid hormone plays a crucial role in the growth and development of the retina, which is evident in the smaller and thinner retinas observed in hypothyroid rats [21]. Moreover, there may exist a correlation between hypothyroidism and elevated vascular resistance, impaired endothelial function, and an increased tendency for blood clotting. Various factors collectively play a role in the heightened occurrence of peripheral arterial disease among diabetic individuals with subclinical hypothyroidism. Further, subclinical hyperthyroidism is most commonly caused due to excessive thyroid hormone therapy or Grave’s disease or autonomously functioning thyroid nodules. Subclinical hyperthyroidism is also associated with diabetes mellitus [22]. Thus, treating the subclinical hyperthyroidism may help in decreasing the risk of diabetes mellitus [23].

Hyperthyroidism and hypothyroidism on insulin resistance

Kim et al. (2002) has reported that thyroid hormones have a negative correlation with insulin resistance, which indicates that thyroid hormones are associated with sensitivity of tissues to insulin. Thyroid hormone and insulin have an important role in glucose metabolism at the cellular and molecular levels [24]. Subclinical hypothyroidism is reported to be associated with elevated fasting hyperinsulinemia before insulin resistance becomes evident in patients with subclinical hypothyroidism [25]. Further, many reports suggest that hyperthyroidism promotes insulin resistance. Diabetic patients with hyperthyroidism have been shown to have poor glycemic control. Also, patients with thyrotoxicosis have been shown to have increased glycemic index [26]. In patients with hyperthyroidism, the half-life of insulin is reduced due to an increased rate of degradation as well as enhanced release of biologically inactive insulin precursors [27]. Therefore, untreated hyperthyroidism and hypothyroidism affect the management of diabetes in patients. A systematic approach to thyroid testing in patients with diabetes is recommended.

Thyroid hormone affecting glucose homeostasis

Thyroid hormone (TH) has been recognized for its impact on glucose regulation for a considerable period [28]. It has been documented that TH plays a role in influencing glucose metabolism across various organs including the gastrointestinal tract, liver, pancreas, adipose tissue, skeletal muscles, and the central nervous system [29] [30]; additionally, in the development of pancreatic β cells [31]. A summary of thyroid hormone and its effect on peripheral organs are listed in ([Table 1]).

Table 1 Effect of glucose on various organs during hyperthyroidism and hypothyroidism [28] [30].

Organ	Process	Hyperthyroidism	Hypothyroidism
GIT	Glucose absorption Motility	Increases Increases	Decreases Decreases
Liver	GLUT2 expression Glucose intake Glucokinase activity Glycogen synthesis Glycogen storage Enzyme’s activity in hexose Monophosphate shunt Glycolysis Pyruvate dehydrogenase Enzyme activity Mitochondrial activity Mitochondrial biogenesis Gluconeogenesis Glycogenolysis	Increases Increases Increases Decreases Decreases Increases No effect Decreases Greatly increases Greatly increases Greatly increases Greatly increases	Decreases Decreases Decreases Increases Increases Decreases No effect Decreases Decreases Decreases Decreases Decreases
Skeletal muscles	GLUT4 UCP3 Glucose uptake Contractibility	Upregulates Increases Increases Increases	Downregulates Decreases Decreases Decreases
Adipose tissue	Lipolysis Thermogenesis	Increases Increases	Decreases Decreases
Beta-cells	Insulin	Increases	Decreases

Gastrointestinal tract

Glucose and other monosaccharides are lipophobic and thus require a special carrier for their transport. In the gastrointestinal tract glucose uptake is facilitated against the concentration gradient by sodium glucose cotransporter 1 (SGLT1) present in the apical region of the intestinal lumen [32]. It transports 1 glucose molecule with 2 Na⁺ ions inside the lumen. the balance of Na⁺ ions in enterocytes are maintained by moving Na⁺ out from the lumen by the Na⁺/K⁺ ATPase pump situated on the basolateral side [33]. Then, the glucose enters the blood stream via its movement in the basolateral membrane of the lumen aided by GLUT2 transporters [34] ([Fig. 3]).

Fig. 3 Regulation of SGL1 in response to thyroid hormones. SGLT1 receptor is co-transporter meaning it transport both sodium and glucose across the cell membrane against the concentration gradient located in the apical region of intestinal lumen. An increase in thyroid hormone up-regulates the receptor and a decrease in thyroid hormone down-regulates the SGLT-1 receptor present in GIT.

Hyperthyroidism and gastrointestinal tract

T3 hormones elevate the glucose absorption by the lumen and raise glucose levels in the blood. This is observed due to the upregulation of SGLT1 and GLUT2 mRNA upregulation by the T3 hormones [35]. Excessive levels of thyroid hormone lead to oxyhyperglycemia, which is characterized by a rapid rise in blood glucose levels after consuming oral glucose. This is primarily caused by the stimulation of gastrointestinal mobility and increased glucose absorption by rapid phosphorylation and gastric emptying time [36]. While it is believed that the enhancement of glucose absorption is a consequence of heightened gastrointestinal mobility, it is also possible that thyroid hormone directly affects the gastrointestinal tract [29].

Hypothyroidism and gastrointestinal tract

According to various studies, it is clear that the lower level of thyroid hormones affects the gastro-intestinal absorption of glucose [36] and sluggish motility of the lumen is also observed in conditions like hypothyroidism [37]. Hypothyroidism indirectly contributes to patient’s decreased blood sugar level, because the thyroid hormones affect break down of glucose and energy production. Patients with hypothyroidism have reduced metabolic processes. Therefore, when this metabolic process slows down, excess circulating insulin may cause blood sugar levels to descend and result it led to hypoglycemia [38]. A person with both diabetes and hypothyroidism may experience challenges because antidiabetic medications may experience recurrent episodes of hypoglycemia.

Liver

The liver is the primary location for glucose utilization, with around 50–60% of glucose absorbed from the intestines being processed there [39]. Initially, glucose is phosphorylated to glucose 6-phosphate, which serves as a crucial molecule in various metabolic pathways including oxidative pathways, the pentose phosphate pathway, and glycogen synthesis. Additionally, the liver is responsible for converting excess glucose into fatty acids. Moreover, during fasting, the liver is the sole organ capable of supplying glucose to the bloodstream either through glycogenolysis, where stored glycogen is broken down, or via gluconeogenesis, which involves synthesizing glucose from non-carbohydrate sources such as glycerol, lactate, and alanine [40].

GLUT2 transporter and thyroid disorders

Transport of the glucose into and out of the hepatocytes is done via glucose transporter-2. Thyroid hormones are crucial for controlling the activity of the GLUT2 glucose transporter. They increase the transporter’s activity in hyperthyroidism and decrease it in hypothyroidism [41] [42].

Glucokinase activity and thyroid disorders

In order to maintain the balance, storage and utilization of the glucose in liver, phosphorylation of glucose takes place. In hepatocytes, the glucose gets phosphorylated and gets converted into glucose 6-phosphate. This conversion is done by glucokinase, an isoenzyme of hexokinase, which is the major responsible enzyme of this process [43]. TH plays an important role in glucokinase activity. In hyperthyroid conditions, the elevated level of T3 hormones increases glucokinase activity, while the reverse is observed in hypothyroid conditions [44] [45].

Glycogen synthesis and thyroid disorders

Hepatic glycogen metabolism is tightly controlled by hormones such as insulin and glucagon, glucocorticoids, and catecholamines [46]. Excess of thyroid hormones causes an increase in glycogen phosphorylase activity [47]. Thus, hyperthyroidism results in less glycogen storage while many evidences suggests that glycogen synthesis increases in hypothyroidism [48].

Glucose oxidation and thyroid disorders

Unlike brain and skeletal muscles, liver is not predominant organ for further oxidization of glucose [44]. Thyroid hormones exert their effects on the mitochondrial oxidization of glucose based on the observation of no rate change of enzymatic activity during the glycolysis process [49] [49] [51] activity and expression of enzyme pyruvate dehydrogenase are significantly reduced in hypothyroid condition [52] and hyperglycemic condition is observed during long-term hyperthyroidism due to under expression of pyruvate dehydrogenase leading to the conversion of pyruvate into glucose via gluconeogenesis process [53] [54] ([Fig. 4]).

Fig. 4 Fate of glucose molecule in cytoplasm and mitochondria of hepatocyte. In cytoplasm thyroid hormone increases and decreases the glucokinase activity based on over and under secretion of hormones respectively. In mitochondria thyroid hormone regulates the pyruvate dehydrogenase enzyme activity.

Mitochondrial oxidation in TCA cycle and thyroid disorders

Thyroid hormones have reported effects on mitochondrial oxidation through direct (binding to the binding site of mitochondria) and indirect (binding to another site such as the nucleus) methods [55]. Thyroid hormone is the major responsible hormone for the growth of mitochondria [56]. In hypothyroidism number and size of mitochondria are reduced [57]. Conversely, excess amount of TH is linked with accelerated carbohydrate metabolism leading to energy generation and increased in catabolic and anabolic processes. Both the number and size of mitochondria increase in hyperthyroid conditions [58]. In hepatocytes the mitochondrial biogenesis is induced by TH through activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha) [59] [60].

Gluconeogenesis and thyroid disorder

The liver experiences an increase in gluconeogenesis due to the presence of thyroid hormone. This increase can occur either directly through the effects of thyroid hormone or indirectly through the influence of glucagon or catecholamine. The activity of the enzyme phosphoenolpyruvate carboxykinase (PEPCK) is heightened by THs, resulting in an enhancement of hepatic gluconeogenesis [61]. This leads to an increase in glycogenolysis and hepatic glucose output, ultimately causing hyperinsulinemia and glucose intolerance, which in turn leads to insulin resistance [62].

Skeletal muscles

Skeletal muscles are the major site for the storage of glucose, transported in response to insulin. Initiating glucose phosphorylation, glycogen synthesis, and glucose oxidation are also facilitated by the insulin [5] [63].

GLUT4 transporter and effect of TH

Skeletal muscle is the main tissue that contributes to systemic glucose depletion in postprandial conditions in order to maintain normal glycemia. GLUT4 is the main glucose carrier for skeletal muscles [64]. Thyroid hormones upregulate the GLUT4 transporter, showing some action of TH synergistic to insulin [65].

UPC3 and thyroid disorder

Another target for the T3 in skeletal muscles is mitochondrial uncoupling receptor 3 (UCP3), which is important to note because the reduction of UCP3 results in insulin resistance along with decreased fatty acid oxidation and a less stimulated AKT/PKB and 5 adenosine monophosphate-activated protein kinase (AMPK) signaling [66].

Muscles contractibility, glycolysis, oxidative effect, and thyroid hormones

The sarcoplasmic endoplasmic reticulum (SERCA) is responsible for the contraction of skeletal muscles. It has been suggested that the TH increases the contractibility of skeletal muscles by affecting SERCA1a and SERCA1b protein along with a concomitant increase in glycolytic and oxidative capacity of the muscles [67] [68]. Recent research has investigated the theory that heightened blood flow rates in hyperthyroidism could potentially conceal a malfunction in insulin-triggered glucose disposal within the muscle. This could be attributed to abnormalities in the intracellular pathways of glucose metabolism [69]. Thus hyperthyroidism leads to an increase in GLUT4 expression and glucose uptake in skeletal muscle [70].

Adipose tissue

In the adipose tissues, the presence of thyroid hormone stimulates the process of lipolysis [71]. This results in an elevation of serum free fatty acid levels, which in turn leads to the development of insulin resistance. According to various studies, it has been found that thyroid hormones play a crucial role in the mobilization of tissue lipids, particularly in brown adipose tissues (BATs), which serve as the primary source of fuel for heat production. Adipocytes releases proinflammatory mediators like IL-6, TNF-α, and several adipokines under the influence of hyperthyroidism causing peripheral insulin resistance [72]. The condition of hypothyroidism and reduced levels of thyroid hormones are directly linked to a decrease in thermogenesis within BAT [73]. The combination of heightened lipolysis increased hepatic β-oxidation, and an insulin deficiency can potentially lead to the occurrence of ketoacidosis [74].

Hormone release from adipose tissue: Adiponectin

Adiponectin, the predominant adipokine released by the adipose tissue, possesses significant insulin-sensitizing properties by enhancing glucose uptake and diminishing glucose production by augmenting the insulin sensitivity of both muscle and liver [75]. Reduced levels of adiponectin have been associated with an increased susceptibility to developing type 2 diabetes. Additionally, adiponectin and thyroid hormones exhibit similar biological characteristics, such as promoting thermogenesis and lipid oxidation, leading to a decrease in body fat [76]. There has been a suggestion that the presence of adiponectin could potentially impact the production of thyroid hormones by interacting with the gC1q receptor located in the mitochondria of the thyroid gland [77]. Patients with autoimmune hyperthyroidism have been observed to exhibit elevated levels of circulating adiponectin in the majority of the conducted studies [78]. In patients with Graves’ disease, there is a correlation between elevated levels of adiponectin in the bloodstream and the severity of hyperthyroidism as well as the autoimmune response [79]. However, some studies have reported that adiponectin did not correlate with thyroxin levels, which indicates that insulin resistance associated with hyperthyroidism is not attributed to adiponectin levels [80]. In addition, another study has reported that appropriate treatment of hyperthyroidism is not accompanied by significant changes in circulating adiponectin levels [78].

Skeletal muscles and adipose tissue synergistic effect

There is well-known communication between skeletal muscles and adipose tissue through fatty acids, but adipose tissue can also crosstalk with skeletal muscle through adipokines. These are responsible for the insulin sensitivity of skeletal muscles and similarly, skeletal muscles also release myokines, which in excess amounts cause insulin resistance. Interestingly, both hypothyroidism and hyperthyroidism affects the adipokines-myokines interaction and contributes in insulin resistance [72].

Pancreas

Thyroid hormones are responsible for the growth of pancreatic islet cells, and TH binds to TR α1 and TR β1 receptors [81]. The secretion of insulin by beta cells is directly regulated by thyroid hormones. In cases of hypothyroidism, the secretion of insulin in response to glucose is reduced, while hyperthyroidism enhances the beta cells’ response to glucose. T3 has a significant impact on insulin production by pancreatic beta cells within the normal range. This is because neonatal beta cells possess TH receptors, and their exposure to T3 facilitates the activation of the transcription factor MAFA, which in turn stimulates the maturation of beta cells [82]. However, in hyperthyroid rats, the pancreas enlarges, but both the capacity of the islets and the overall number of insulin-positive cells decrease [83]. The decline in islet function and reduced production of insulin in response to glucose are primarily attributed to a decrease in beta cell mass and dysfunction of the insulin secretory pathway. This pathway involves two crucial components: ATP-sensitive K⁺ channels and L-type Ca2⁺ channels. It is important to note that abnormal glucose tolerance in this case is not a result of insulin resistance, but rather a defective response of pancreatic beta cells to glucose [81]. Additionally, thyroid hormone increases the degradation of insulin and thyrotoxicosis leads to an increase in insulin clearance. Furthermore, thyroid hormone stimulates the secretion of glucagon by pancreatic alpha cells [84].

Thyroid disorders and its effect on insulin

Hyperthyroidism

During hyperthyroidism, the degradation rate of insulin is accelerated, leading to a decrease in its half-life. This is primarily caused by an augmented release of biologically inactive insulin precursors [85]. Increased proinsulin levels in response to a meal were observed in individuals with untreated Graves’ disease. Additionally, untreated hyperthyroidism was found to be linked with a decreased C-peptide to proinsulin ratio, indicating a potential underlying issue in proinsulin processing. Additionally, individuals with hyperthyroidism exhibit heightened insulin degradation and expedited insulin clearance. Individuals with hyperthyroidism have a higher likelihood of experiencing severe hyperglycemia. In cases where there is a lack of insulin, increased lipolysis and hepatic β-oxidation can lead to the development of ketoacidosis [86]. Thyrotoxicosis has the potential to trigger diabetic complications, including endothelial dysfunction, which in turn elevates the likelihood of cardiovascular comorbidities [87].

Hypothyroidism

Patients suffering from hypothyroidism may experience insulin resistance. Diminished levels of thyroid hormones have a significant impact on multiple organs. In hypothyroidism, various mechanisms impact glucose metabolism, leading to a decrease in liver glucose production and decrease in glucose uptake by the gastrointestinal tract [88]; also causes insulin resistance, and leads to decreased insulin-stimulated glucose transport, glucose disposal, and utilization in peripheral tissues. Additionally, there is a reduction in the rate of glucose oxidation and glycogen production [89]. About beta cell function, there is an augmentation in glucose-induced insulin secretion, and numerous research studies have indicated a rise in insulin levels in individuals with hypothyroidism [90]. Additionally, the renal system plays a role in prolonging the half-life of insulin by reducing insulin clearance. For individuals with both diabetes mellitus (DM) and hypothyroidism who are undergoing insulin treatment, it may be necessary to make adjustments to the insulin dosage. The decreased renal insulin clearance results in elevated insulin levels, which in turn may lead to lower requirements for externally administered insulin [91].

Thyroid hormones and their interaction with other hormones

The interaction between thyroid hormones and adipose tissue hormones namely adiponectin and leptin can potentially impact carbohydrate mechanisms in two ways. First, thyroid hormones have a significant impact on the metabolism of adipose tissue. Second, as thyroid hormones lead to insulin resistance, studying the production rates and plasma levels of these cytokines could offer valuable insights into the underlying mechanism [92]. Adiponectin, which is already discussed above, being the most abundant adipokine released by adipose tissue, plays a crucial role in enhancing insulin sensitivity. It has been observed that individuals with low levels of adiponectin are at a greater risk of developing type 2 diabetes [93].

Leptin

The hormone leptin is believed to have a role in regulating energy balance and body weight through neuroendocrine mechanisms. It has demonstrated the ability to enhance the activity of peripheral type 2 deiodinase, resulting in an increased availability of T3 to peripheral tissues. Consequently, leptin might contribute to the elevation of T3 levels, potentially exacerbating hyperthyroidism [94]. In patient with DM there has been increased in leptin hormones, leading to increase in TSH level, which amplifies the production of T3.

Clinical complications in patients suffering from both TD and DM

Glycated albumin

In addition to glycated hemoglobin, glycated albumin is also utilized as a marker for glycemic control in individuals with diabetes. However, it is important to note that glycated albumin is influenced not only by glycemic control but also by albumin metabolism. Furthermore, thyroid hormone plays a role in albumin catabolism. As a result, patients with hypothyroidism tend to exhibit higher levels of serum glycated albumin, while those with hyperthyroidism tend to have lower levels. A significant positive correlation has been observed between serum glycated albumin and TSH levels, while an inverse correlation has been found between serum glycated albumin and free T3 or free T4 levels. Therefore, it is crucial to carefully evaluate serum glycated albumin levels in diabetic patients with thyroid dysfunction [95].

Dietary plan

The diet therapy designed for individuals with diabetes strongly advises the consumption of seaweed due to its low-calorie content and abundance of minerals and dietary fiber. Nevertheless, it is important to note that certain types of seaweed, particularly Kombu or kelp, contain high levels of iodine. Excessive intake of iodine can potentially lead to thyroid dysfunction in susceptible patients, particularly those with autoimmune thyroid diseases [28] [29].

Various hypoglycemic agents affecting the interplay

Treatment of type 2 diabetes mellitus with insulin therapy and drugs like metformin, sulfonylureas, and thiazolidinediones affects the thyroid hormone regulation and may cause thyroid dysfunction or related disorders ([Table 2]).

Table 2 Effect of antidiabetic agents and insulin therapy on thyroid function in type 2 diabetes mellitus patient.

Drugs	Effects	Reference
Metformin	Reduces TSH levels in serum. Inhibits mTOR pathway. Downregulation of hypothalamic AMPK resulting in reduced T3 and TSH.	[97] [103]
Sulfonylureas	Reduces iodine uptake by the thyroid gland. Goitrogenic and hypothyroidism effect in the first generation of sulfonylurea.	[109] [111]
Thiazolidinediones	Increases eye protrusion in Graves orbitopathy when taking pioglitazone. Reduces risk of thyroid cancer in T2DM patients taking rosiglitazone.	[118] [120]
Dipeptidyl peptidase-4 inhibitors	Administration of DPP4 inhibitors increases the severity of Graves’ disease.	[122] [123]
SGLT-2 inhibitors	SGLT-2 inhibitors have a significant protecting effect on thyroid dysfunction, particularly hyperthyroidism.	[125] [126]
Glucagon-like peptide-1 agonists	GLP-1 receptor agonists do not have any significant effect on the risk of thyroid cancer, hyperthyroidism, hypothyroidism, thyroiditis, and goiter.	[128] [129]
Insulin Therapy	Insulin treatment restores thyroid status in diabetic patients. Insulin enhances the levels of FT4 and suppresses the level of T3 by inhibiting the conversion of T4 to T3 in the liver. Hypothyroidism slows down the metabolism of insulin therefore a person with diabetes and hypothyroidism may require a lower dose of insulin for their treatment.	[131]

Metformin

Metformin is the first choice of drug for T2DM with only a few adverse effects like abdominal pain, diarrhea, nausea, and indigestion. In 2006, it was noted that the TSH level in the patient with T2DM and primary hypothyroidism decreased upon using the metformin [96]. Other studies also suggest that the metformin decreases the serum TSH levels [97] [98]. A meta-analysis study of before and after treatment of metformin and TSH levels resulted in reduced serum TSH levels in hypothyroidism and subclinical hypothyroidism [99] [100]. There is no alteration in FT4 and FT3 levels during metformin treatment. Moreover, a reversible effect was observed when the metformin was discontinued [101]. Metformin mainly acts by suppressing hepatic gluconeogenesis via activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). In the hypothalamus, AMPK also plays an important role and the blood-brain barrier property of metformin is well established [102] suggesting the inhibition of central AMPK resulting in lower secretion of T3 and TSH [103]. Deiodinase type 2 (D2) catalyzes T4 to T3 in glial cells, astrocytes, and tanycytes in the mediobasal hypothalamus region. During insulin resistance, polymorphism of D2 takes place, and conversion of T3 from T4 decreases. It was observed that metformin enhances the activity of D2 at pituitary levels in hypothyroid patients [104] [105]. Hyperinsulinemia and insulin resistance are the major reasons for the high prevalence of thyroid cancer. Metformin has been recorded with antimitogenic and proapoptotic effects in thyroid carcinoma cell lines [106] along with a 30% reduction in thyroid nodule size [107]. Furthermore, observation of treatment with metformin in diabetic patients has suggested downregulation of mTOR pathway, which can lead to metastatic medullary thyroid cancer (MTC) [107] [108] ([Fig. 5]).

Fig. 5 Metformin affecting mTOR pathway. AKT: Protein kinase B; ROS: Reactive oxygen species; P53: Tumor protein 53; IGF1: insulin-like growth factor 1; IRS-1: Insulin receptor substrate 1; RAG: Recombination activating genes; TSC2: Tuberous sclerosis complex 2; RHEB: Ras homologue enriched in brain.

Sulfonylurea

Sulfonylurea is reported to exhibit antithyroid effects [109] [110] and iodine uptake by thyroid gland reduces, while its weight gets increased [111] [112]. The high prevalence of hypothyroidism has been linked to long term use of first generation sulfonylurea medication [111]. First generation sulfonylureas (chlorpropamide and tolbutamide) inhibit the binding of T3 and T4 to T4 binding globulin through the IV route; no effects are observed in the oral route [113] and chlorpropamide shows goitrogenic effects according to [114]. Second generation (glibenclamide and gliclazide) do not influence TH regulation [115] [116].

Thiazolidinediones

The thiazolidinediones (TZDs) are one of the most commonly used oral hypoglycemic agents. They are agonist of nuclear hormone receptors, peroxisome proliferator-activated receptor γ (PPAR-γ) [117]. In graves orbitopathy (GO) the expression of PPAR-γ is observed in adipose and connective tissue. TZD brings and differentiate orbital fibroblast into mature lipid-laden adipocytes, suggesting that accelerated level of PPAR-γ is involved in pathogenesis of GO induced by TZDs [118] [119]. An increase in eye protrusion with GO was observed in T2DM in patients taking pioglitazones while rosiglitazone in patients might reduce the risk of thyroid cancer [120]. Patients with active Graves’ orbitopathy (GO) should avoid thiazolidinediones due to the increased risk they pose. Additionally, individuals with type 2 diabetes mellitus (T2DM) and Graves’ disease should receive thiazolidinediones with caution to prevent adverse effects, as discontinuation of these medications can lead to irreversible exacerbations of GO [121].

Dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase-4 inhibitors stimulate pancreatic insulin secretion by elevating glucose-dependent insulinotropic polypeptide levels. Studies reported dipeptidyl peptidase-4 inhibitors exacerbate Graves’ disease. Dipeptidyl peptidase-4 is expressed on the surface of T cells and T cells have been implicated in the initiation and amplification of autoimmunity [122]. Moreover, Graves’ disease is an autoimmune disease that occurs due to the overproduction of thyroid hormone due to upregulated thyroid stimulation by thyroid-stimulating hormone receptor antibodies. Therefore, inhibition of dipeptidyl peptidase-4 might affect the thyroid function [123].

SGLT-2 inhibitors

SGLT2 inhibitors bind to SGLT2 receptors present in proximal tubules of the kidney, which results in beneficial effects in patients of T2DM by preventing its reabsorption of glucose from the urine [124]. Interestingly, thyroid dysfunction has also been linked to cognition and depression. The thyroid gland plays a vital role in regulating metabolism and have profound effects on the CNS. There is a complex interplay between glucose metabolism, thyroid function, and brain health. Both hyperthyroidism and hypothyroidism can manifest with cognitive impairment and mood disorders. There are many studies showing that SGLT2 inhibitors increased risk of mood disturbances and cognitive decline in patients with T2DM by increasing TSH levels and these changes in TSH levels can influence cognitive function [125] [126].

Glucagon-like peptide-1 agonists

Glucagon-like peptide 1 receptor agonists have shown significant improvement in hyperglycemia and diabetes-related outcomes such as overweight, obesity, cardiovascular and renal impairment, and nonalcoholic fatty liver disease. A preclinical study reported that GLP-1 receptors are widely expressed on parafollicular C-cells membrane and binding to the GLP-1 receptor induces cell proliferation. It also stimulates the synthesis and secretion of calcitonin in a cAMP-dependent manner. Therefore, GLP-1 may promote thyroid carcinogenesis [127]. However, insufficient evidence indicates the potential cancerogenic effect in humans’ glucagon-like peptide 1 receptor agonists. Therefore, possible cause-effect and dose-dependent relationships between chronic administration of glucagon-like peptide 1 receptor agonists and the risk of thyroid cancer in T2DM have not been ruled out [128]. Further, glucagon-like peptide 1 is also associated with increase in T3 levels by upregulation of iodothyronine deiodinase expression. In addition, a clinical study showed that Glucagon-like peptide 1 receptor agonists reduce serum TSH levels in diabetic patients without thyroid disease [129].

Insulin therapy

Insulin resistance causes increases in T3 compared to insulin sensitivity [130]. The administration of exogenous insulin can have an impact on thyroid function in individuals with T2DM. Insulin enhances the levels of FT4 and suppresses the level of T3 by inhibiting the hepatic conversion of T4 to T3. Insulin modulates TRH and TSH levels by exerting a negative regulatory effect [131]. Therefore, insulin treatment should be adjusted in patients with diabetes after the occurrence of thyroid dysfunction.

Drugs used in thyroid disorders

Various adverse effects related to diabetes mellitus and blood glucose regulation of hyperthyroidism and hypothyroidism disorder treatments are listed in [Table 3].

Table 3 Drugs used in thyroid disorders and their effect on glucose metabolism [133] [137].

Drugs	Effects
Methimazole or carbimazole	Causes hypoglycemia Increases risk of insulin autoimmune syndrome (IAS)
Levothyroxine	Reduces TSH levels Increases glucose clearance

Methimazole or carbimazole

Antithyroid drugs like methimazole and carbimazole are most widely used in two ways, primarily for treating hyperthyroidism and as a preparative treatment before radiotherapy and surgery. They are widely used in the treatment of grave disorders [132]. The use of methimazole or carbimazole in Graves disorder causes hypoglycemia and the sulfhydryl group present in the drug suggests a risk of insulin autoimmune syndrome [133] [134]. This observation is also strengthened by the case reports [135] [136].

Levothyroxine

Thyromimetics is a promising therapy in treating hypothyroidism. The long term supplementation with levothyroxine is observed to enhance glucose clearance and decrease the onset of type 1 diabetes mellitus [137]. Along with effects like a significant reduction in TSH and blood glucose levels [138].

Conclusion

All the studies and observations conducted suggest strong nexus of thyroid disorder and diabetes mellitus interplay. The factor amounts of glycated albumin present in hypo- and hyperthyroidism is linked with diabetic conditions. Furthermore, it is advisable to avoid dietary sources such as kelp in patients with diabetes mellitus and thyroid disorder due to the presence of high iodine. Both facts serve as additional evidence of the co-occurrence of both endocrinopathies. Outcomes like increases in the severity of diseases in patients, various metabolic changes altogether make treatment difficult. Both high and low level of thyroid hormones results in insulin resistance. Elevated levels increase glucose uptake and regulation in peripheral tissues, further leading to ketoacidosis, while reduced levels result in decreased glucose absorption resulting in prolonged insulin clearance in hepatic system. Similarly, type 2 diabetes mellitus interferes with thyroid hormone levels by reducing thyroid stimulating hormone levels, making management of disorders difficult, along with the rise in prevalence of comorbid conditions of both. Among medications, only metformin shows positive results in treating thyroid disorder, other oral hypoglycemic agents and insulin worsen the disorder, resulting in more chances of hypothyroidism because of a decrease in TSH and serum T3 levels compared to hyperthyroidism in diabetic patients, while antithyroid drug worsens diabetic conditions.

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