Research Blog
Thyroid hormones regulate glucose homeostasis through their effects on the pancreas, liver, GI tract, adipose tissue, skeletal muscle, and the central nervous system.
Not surprisingly, thyroid hormone status and diabetes mellitus (DM) are closely related, and thyroid disorders have a higher prevalence in those with diabetes compared to the general public and vice versa. A meta-analysis of all data from 10,920 subjects with diabetes mellitus revealed an 11% prevalence of thyroid disease.
Thyroid dysfunction is especially prevalent in those with type 1 DM and should be screened for regularly, especially in those positive for TPO antibodies.
Blood glucose depends on:
- Rate of gastric emptying
- Hepatic breakdown of glycogen (glycogenolysis)
- The balance of neuropeptides and hormones released from the pancreas, liver, intestine, adipose tissue, muscle, and brain
- Insulin and glucagon, primarily
- Amylin, glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), epinephrine, cortisol, and growth hormone (GH) all participate in glucose regulation
Post-meal versus fasting glucose
Post meal:
- After a meal, glucose is absorbed, and plasma glucose levels rise.
- Increasing glucose levels stimulate pancreatic β-cells to secrete insulin. Insulin increases glucose disposal by glycogen synthesis and lipogenesis in the liver
- Insulin promotes the uptake of glucose and conversion to glycogen or triglycerides by skeletal muscle and adipose tissue
Fasting:
- During fasting, glucagon is released to increase blood glucose levels through glycogenolysis.
- When fasting is prolonged, glucose is produced by hepatic gluconeogenesis
Maintenance of blood glucose levels by insulin and glucagon in fed & fasting states.
Thyroid effects on glucose homeostasis
Thyroid hormone:
- Affects pancreatic beta cell development in early infancy and function later in life
- Enhances glucose absorption by increasing gastrointestinal motility
- Increases hepatic glucose output through increased hepatic expression of glucose transporter 2 (GLUT2), which stimulates the endogenous production of glucose through an increase in gluconeogenesis and glycogenolysis.
- T3 also increases hepatic gluconeogenesis by increasing the activity of phosphoenolpyruvate carboxykinase (PEPCK), an enzyme that enhances gluconeogenesis.
- Stimulated glycogenolysis and gluconeogenesis induce hyperinsulinemia and glucose intolerance, resulting in peripheral insulin resistance
- Increases lipolysis in adipose tissue, resulting in an increase in free fatty acid that stimulates hepatic gluconeogenesis
- Stimulates insulin secretion by pancreatic β-cells and increases glucagon release by pancreatic α-cells
- Hyperthyroidism increases glucose transporter type 4 (GLUT4) gene expression and glucose uptake in skeletal muscles
- T3 can centrally modulate glucose production through a sympathetic pathway from the hypothalamic paraventricular nucleus (PVN) to the liver.
- T3 in the hypothalamic PVN increases hepatic glucose production, independent of glucoregulatory hormones
Effects of thyroid hormone on glucose metabolism
GLUT4, glucose transporter type 4; PEPCK, phosphoenolpyruvate carboxykinase.
Insulin resistance
Insulin resistance is a decreased metabolic response to insulin in peripheral tissues, including muscle, liver, and adipose tissue.
The pancreas responds to increased blood glucose by secreting more insulin, creating a state of chronic hyperinsulinemia and increased risk of type 2 DM.
Both hypothyroidism and hyperthyroidism can affect insulin resistance and should be assessed further as factors in type 2 DM.
Hypothyroidism
- The prevalence of hypothyroidism in T2DM has been reported to be between 5.7% and 25.3%, depending on age, gender, and iodine status.
- Hypothyroidism impairs glucose absorption from the GI tract and delays peripheral glucose assimilation and hepatic gluconeogenesis
- Decreased glucose disposal in hypothyroidism is likely due to decreased insulin sensitivity in skeletal muscle and adipose tissue
- Deteriorating glucose regulation is seen in subclinical hypothyroidism as well as overt hypothyroidism
- A meta-analysis study revealed that the risk of developing subclinical hypothyroidism increased by 1.93-fold in T2DM patients compared to non-diabetics and that subclinical hypothyroidism may also be associated with an increase in diabetic complications.
- Free thyroxine (T4) levels in the lower end of the reference range are also associated with higher glycosylated hemoglobin (HbA1c) levels in the euthyroid state.
- Restoring thyroid hormone status is associated with an improvement in insulin sensitivity
Hyperthyroidism, thyrotoxicosis
- Hyperthyroidism is more prevalent in those with type 2 DM than in the general US population, i.e., 4.4% versus 1.3%, respectively.
- Excess thyroid hormone can increase:
- Glucose absorption by the GI tract
- Glucose production in the liver via increasing gluconeogenesis and glycogenolysis,
- Concentration of free fatty acids via promotion of lipolysis
- Stimulates insulin secretion and induces hyperinsulinemia, although thyrotoxicosis also accelerates insulin degradation and decreases the half-life of insulin
- Increased hepatic glucose output induces hyperinsulinemia, glucose intolerance, and peripheral insulin resistance.
- Hyperthyroidism precipitates impaired fasting glucose and diabetes and worsens glycemic control in pre-existing T2DM.
- Thyrotoxicosis may rarely precipitate diabetic ketoacidosis in type 1 and type 2 DM when accompanied by insulin deficiency, which can enhance the risk for lipolysis
Hypoglycemia
Glucose must always be available to the brain due to its inability to store it. Low blood glucose, i.e., hypoglycemia, can adversely affect brain function.
Hypothyroidism may cause hypoglycemia due to its effects on hormone balance and nervous system function. Thyroid hormones affect the hypothalamic-pituitary-adrenal (HPA) axis, reduce cortisol and growth hormone secretion, and interfere with the typical response to hypoglycemia.
Pre-existing adrenal insufficiency in those with hypothyroidism can weaken the HPA response to hypoglycemia.
Hypoglycemia is further exacerbated by the reduction in gluconeogenesis and glycogenolysis seen with hypothyroidism.
The bottom line is…
Thyroid function and blood glucose regulation are closely related. Dysfunction in either system should trigger a deeper dive into an individual’s metabolic profile to help them return to optimal health.
Reference
Eom, Young Sil et al. “Links between Thyroid Disorders and Glucose Homeostasis.” Diabetes & metabolism journal vol. 46,2 (2022): 239-256. doi:10.4093/dmj.2022.0013 This is an Open Access article distributed under the terms of the Creative Commons
