Evidence for a relationship between T4 and T3 and glucose metabolism appeared over 100 years ago when the influence of thyroid hormone excess in the deterioration of glucose metabolism was first noticed. Since then, it has been known that hyperthyroidism is associated with insulin resistance. More recently, hypothyroidism has also been linked to decreased insulin sensitivity. The explanation to this apparent paradox may lie in the differential effects of thyroid hormones at the liver and peripheral tissues level. The purpose of this paper is to explore the effects of thyroid hormones in glucose metabolism and analyze the mechanisms whereby alterations of thyroid hormones lead to insulin resistance.
The effects of T4 and T3 have a large impact on glucose homeostasis. This concept was acknowledged by Nobel Prize winner Dr. Bernardo Alberto Houssay in his lecture in 1947 “
In the century that has elapsed, since the first observations of uncontrolled glucose metabolism in thyrotoxic diabetic patients [
In this paper, we summarize the effects of thyroid hormones in glucose metabolism and its alterations when thyroid dysfunction is present.
Effects of thyroid hormones on glucose metabolism in euthyroid (solid lines), hyperthyroid (rough-dashed lines), and hypothyroid conditions (fine-dashed lines). TH: thyroid hormones.
Direct effects of T3 on genes that regulate glucose homeostasis at the liver and peripheral tissues (muscle, fat tissue, and fibroblasts).
Gene | Expression | Site | Net effect |
---|---|---|---|
glucose-6-phosphatase [ | Increase | liver | Increase gluconeogenesis and glycogenolysis |
protein kinase B (Akt2) [ | decrease | liver | Decrease glycogen synthesis |
Increase | liver | Increase gluconeogenesis and glycogenolysis | |
inhibitory G protein (Gi) [ | decrease | liver | Increase gluconeogenesis and glycogenolysis |
phosphoenolpyruvate carboxykinase (PEPCK) [ | Increase | liver | Increase gluconeogenesis |
pyruvate carboxylase (PC) [ | Increase | liver | Increase gluconeogenesis |
GLUT2 [ | Increase | liver | Increase glucose output |
malic enzyme [ | Increase | liver | lipogenesis |
Carbohydrate-response element-binding protein (ChREBP) [ | Increase | liver and fat tissue | lipogenesis |
GLUT1 [ | Increase | peripheral tissues | Increase glucose transport (basal) |
GLUT4 [ | Increase | peripheral tissues | Increase glucose transport (insulin-induced) |
Increase | Peripheral tissues | Increase lipolysis | |
phosphoglycerate kinase (PGK) [ | Increase | peripheral tissues | Increase glycolysis |
Hypoxia-inducible factor 1 (HIF-1 | Increase | peripheral tissues | Increase glycolysis |
PPAR gamma coactivator-1 alpha (PGC-1 alpha) [ | Increase | peripheral tissues | Increase mitochondrial biogenesis and function |
uncoupling protein 3 (UCP3) [ | Increase | peripheral tissues | Increase mitochondrial energy expenditure |
Thyroid receptor-mediated effects on gene transcription and translation are key in the regulation of glucose metabolism. According to the results of studies with complementary DNA (cDNA) microarray analysis in mouse liver, this organ is a major target of thyroid hormones. Several genes involved in gluconeogenesis, glycogen metabolism, and insulin signaling that are regulated by thyroid hormones have been identified. In the study by Feng et al. [
Another mechanism, whereby thyroid hormones are known to increase hepatic glucose output, is through increased hepatic expression of the glucose transporter GLUT2 [
It has been previously reported that, despite an expected resistance towards the insulin inhibitory effect on gluconeogenesis, the transcription of several enzymes involved in lipid synthesis or lipid metabolism is increased in hyperinsulinemic, insulin-resistant mice [
As a result of the long time quest for thyroid analogs that possess the favourable actions on metabolism without the unwanted thyroid cardiac effects, an indirect way of learning about T3 action in the different tissues has emerged [
To summarize, all these findings have helped to understand that thyroid hormones have insulin antagonistic effects at the liver that lead to an increased glucose hepatic output, via an enhanced rate of gluconeogenesis and glycogenolysis. With regards to lipid metabolism, both lipogenesis and lipolysis are stimulated by T3. However, in the context of insulin resistance, the conversion of glucose into fatty acids together with nonsuppressed gluconeogenesis is simply perpetuating the hyperinsulinemic state. Furthermore, nutritional influences, such as those of high-fat diets, should also be taken into consideration as modifiers of the effects of thyroid hormones on insulin sensitivity.
Opposite to what occurs at the liver level, at peripheral tissues, thyroid hormones have been shown to exert some of their actions synergically with insulin. The upregulation of the expression of genes such as GLUT-4 [
In skeletal muscle, the main site of insulin-mediated glucose disposal, glucose transporter GLUT4, is induced by T3, revealing that it can increase basal and insulin-stimulated glucose transport in this tissue [
Liver actions of the naturally occurring thyromimetic analog T2 have been discussed above. However, T2 actions have been also explored in skeletal muscle [
The result of cDNA microarray analysis on skeletal muscle of a group of healthy men receiving 75
Skin fibroblasts have been also used to study thyroid hormone-responsive genes involved in metabolism in human cells. Although they are not as metabolically active as hepatic cells, they are easily obtained and also, thyroid hormone-responsive. In cultured human fibroblasts, Moeller et al. [
At the cellular level, thyroid hormones can also increase mitochondrial biogenesis, fatty acid oxidation, and TCA cycle activity [
It has been shown that the hypothalamus can modulate endogenous glucose production by using functionally reciprocal sympathetic and parasympathetic autonomic outputs to the liver [
Thyrotoxic subjects frequently show impaired glucose tolerance. This is a result of increased glucose turnover with increased glucose absorption through the gastrointestinal tract, postabsorptive hyperglycemia, elevated hepatic glucose output, with elevated fasting and/or postprandial insulin and proinsulin levels, elevated free fatty acid concentrations and elevated peripheral glucose transport and utilization. The literature about this topic is vast and has been previously comprehensively reviewed by Dimitriadis and Raptis [
Thyrotoxicosis has been reported to increase endogenous glucose production in the liver in the basal state and to decrease hepatic insulin sensitivity in humans [
The interpretation of the effects of hyperthyroidism on glucose utilization by peripheral tissues is by far the most complex issue on this topic. On one hand, the rates of glucose uptake in peripheral tissues have been found increased by thyroid hormones, suggesting that glucose utilization is highly increased, specially in skeletal muscle [
Although glucose intolerance in hyperthyroidism can be easily explained by hepatic insulin resistance without involvement of peripheral tissues, impaired insulin-stimulated peripheral glucose uptake has also been proven in some studies. By means of the arteriovenous difference technique in the forearm muscles of hyperthyroid subjects after the consumption of a mixed meal, it has been clearly demonstrated that muscle blood flow is increased, masking a defect in insulin-stimulated glucose uptake [
Alternative explanations for peripheral insulin resistance in hyperthyroidism include an increased secretion of bioactive mediators (adipokines) such as interleukin 6 (IL6) and tumour necrosis factor a (TNF
In hyperthyroidism, decreased, normal, or even increased levels of plasma insulin have been reported [
With regards to glucagon, its secretion and metabolic clearance rates have been reported increased, explaining the normal fasting plasma levels described in hyperthyroidism [
Subclinical hyperthyroidism has also been associated with insulin resistance [
Although seldom happening, hypothyroid patients can experience hypoglycaemia. This phenomenon can be interpreted in the light of reduced levels of gluconeogenesis leading to decreased liver glucose output [
Studies performed in adipocytes and skeletal muscle of rats made hypothyroid have shown that these tissues are less responsive to insulin with regards to glucose metabolism [
Insulin resistance was confirmed in another study of rats with mild hypothyroidism [
Adipocyte-myocyte crosstalk by adipokines has been reported to play a significant role in skeletal muscle insulin resistance and may partially explain insulin resistance present in hypothyroidism [
Compared to the number of reports about insulin resistance in hyperthyroid patients, there are relatively fewer studies in humans dealing with the effects of hypothyroidism on glucose metabolism. Rochon et al. [
Dimitriadis et al. [
Some negative results, however, in this field have been reported. A previous study in overt hypothyroid patients based on the homeostasis model assessment (HOMA-IR) [
With regards to subclinical hypothyroidism, insulin resistance has been demonstrated in some [
Thyroid hormones have a large impact on glucose metabolism. A direct regulation on thyroid responsive genes at the target organ has been described and more recently an indirect effect involving hypothalamic pathways that regulate glucose metabolism via control of the sympathetic nervous system has been reported. Furthermore, thyroid hormone effects can be insulin agonistic, such as demonstrated in muscle or antagonistic such as observed in the liver. In hyperthyroidism, dysregulation of this balance may end in glucose intolerance mainly due to hepatic insulin resistance. In hypothyroidism the results are less evident. However, the available data suggest that insulin resistance is present mainly at the peripheral tissues. Possible explanations hypothesized to explain this phenomenon span from the dysregulation of mitochondrial oxidative metabolism to the reduction of blood flow in muscle and adipose tissue under hypothyroid conditions.