Thyroid hormones regulate systemic glucose metabolism through incompletely understood mechanisms. In a recent article published on Oct. 27, 2022 in Nature Communications, a team led by Dr. YING Hao at Shanghai Institute of Nutrition and Health of Chinese Academy of Sciences, shows that hepatic thyroid hormone receptor β mediates the effects of the thyroid hormone on systemic glucose homeostasis by modulating GLP-1 levels through suppression of CYP8B1 expression and bile acid-mediated inhibition of intestinal FXR signalling.  

Type 2 diabetes, a complex endocrine and metabolic disorder characterized by hyperglycemia arising from a deficient insulin secretion in the context of insulin resistance. As type 2 diabetes has a multifactorial pathogenesis, there is an urgent need for differently acting pharmacological compounds at different stages of the disease. Incretin effect is essential for the postprandial glucose controls, as it is responsible for 50–70% of insulin secretion after oral glucose intake in non-diabetic subjects. GLP-1 accounts for most of the incretin effect after an oral glucose load and has emerged as a viable therapeutic target for the treatment of type 2 diabetes mellitus.  

The main active forms of thyroid hormone (TH) include T3 and T4. T3 is the most active form and its biological function is mainly mediated by TH receptor (TR). TH has a profound effect on carbohydrate metabolism; however, the underlying mechanisms are uncertain.   

In this study, researchers demonstrated that improved glucose metabolism in hypothyroid mice after T3 treatment is accompanied with increased glucagon-like peptide-1 (GLP-1) production and insulin secretion, while co-treatment with a GLP-1 receptor antagonist attenuates the effects of T3 on insulin and glucose levels. By using mice lacking hepatic TRβ and a liver-specific TRβ-selective agonist, researchers demonstrated that TRβ-mediated hepatic TH signalling is required for both the regulation of GLP-1 production and the insulinotropic and glucose-lowering effects of T3. Moreover, administration of a liver-targeted TRβ-selective agonist increases GLP-1 and insulin levels and alleviates hyperglycemia in diet-induced obesity.   

Mechanistically, T3 suppresses the CYP8B1 expression, resulting in increased the levels of Farnesoid X receptor (FXR)-antagonistic bile acids, thereby potentiating GLP-1 production and insulin secretion by repressing intestinal FXR signalling. T3 correlates with both plasma GLP-1 and fecal FXR-antagonistic bile acid levels in people with normal thyroid function.   

In a word, this new study reveals a role for hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism.  

This work was mainly supported by National Natural Science Foundation of China and National Key Research and Development Program of China. 

Role of hepatic TH signaling in the regulation of glucose homeostasis. (Image by Dr. YING Hao’s team)  

Media Contact:
WANG Jin
Shanghai Institute of Nutrition and Health,
Chinese Academy of Sciences
Email: wangjin01@sinh.ac.cn
Web: http://english.sinh.cas.cn/