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T2DM is a complex endocrine and metabolic disease with a heterogeneous pathology characterized by the interaction of genetic and environmental factors, as well as varying degrees of insulin resistance and other endocrine disorders. Hyperglycemia is the basic feature of T2DM, so achieving normal blood glucose levels becomes the main goal of T2DM treatment.

GLP-1 (glucagon-like peptide 1) is an intestinal hormone that regulates blood glucose levels by promoting insulin secretion in a glucose-dependent manner and inhibiting gastric emptying and feeding. GLP-1 analogs and drugs that prevent GLP-1 degradation have been used to treat T2DM in recent years. As a result, a thorough investigation of the mechanism of GLP-1 endogenous release and the regulation of glucose homeostasis will contribute to the development of new theoretical foundations and targets for the diagnosis and treatment of T2DM.

T3 and T4 are the most active forms of thyroid hormone (TH), with T3 being the most active and its biological function primarily mediated by the TH receptor (TR). TR is a ligand (T3)-dependent transcription factor with two isoforms that belongs to the nuclear receptor superfamily. TR is abundant in tissues such as the heart, bone, muscle, and fat, whereas TR is mostly found in the liver, kidney, pituitary gland, and other organs. The thyroid gland has a significant effect on glucose metabolism, but the underlying mechanism of action is unknown because thyroid hormone effects on glucose tolerance and insulin sensitivity in different tissues may have different effects on blood glucose levels in the body.

On October 27, 2022, Ying Hao’s group at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences published a research paper online in Nature Communications, entitled “Hepatic thyroid hormone signaling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism”.

Thyroid hormone was found to be able to establish a link with glucose homeostasis via GLP-1 in this study. Activation of the hepatic thyroid hormone signaling pathway has a proinsulin secretory and glucose lowering effect by altering the composition of bile acids via CYP8B1 inhibition, increasing the level of non-12-hydroxy bile acids with FXR antagonism, and thus increasing GLP-1 production via inhibition of the intestinal FXR signaling pathway, indicating that liver-targeted TR agonists are feasible for the treatment of type 2 diabetes in the future.

The active form of thyroid hormone (TH), triiodothyronine (T3), was found to significantly promote the secretion of GLP-1 and insulin, thereby improving glucose homeostasis in a hypothyroid mouse model. The ability of GLP-1 receptor antagonists to inhibit T3 effects on insulin secretion and blood glucose suggests that T3 regulation of glucose homeostasis is dependent on GLP-1.

Using a transgenic mouse model with liver tissue-specific knockout of thyroid hormone receptor β (TRβ) and liver-targeted TRβ-selective agonists, this study further revealed that the hepatic TRβ-mediated TH signaling pathway is essential for T3 to regulate GLP-1 and insulin secretion and for T3 to lower blood glucose. Similarly, in a diet-induced obese mouse model, TRβ-selective agonists targeting the liver were also able to increase insulin and GLP-1 levels and lower blood glucose. In terms of molecular mechanisms, T3 alters the composition of bile acids by inhibiting hepatic CYP8B1 expression levels and increases the proportion of bile acids with farnesol X receptor (FXR) antagonism, thereby inhibiting the intestinal FXR signaling pathway and ultimately promoting the secretion of GLP-1 and insulin.

In a population with normal thyroid function, this study discovered a physiological correlation between T3 levels and both GLP-1 levels and FXR-antagonistic bile acid levels. The study demonstrates the importance of thyroid hormones in maintaining glucose homeostasis and reveals a novel mechanism by which the hepatic TH-TR signaling pathway regulates GLP-1 production via bile acid-mediated FXR antagonism, providing a theoretical foundation for the development of new therapies for T2DM and related metabolic diseases.

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