Nature sub-journal: Ying Hao's team reveals a new mechanism by which thyroid hormones regulate blood glucose homeostasis

Type 2 diabetes mellitus (T2DM) is a complex endocrine and metabolic disease in which genetic and environmental factors interact with heterogeneous pathological features and are accompanied by varying degrees of insulin resistance and other endocrine disorders
.
Hyperglycemia is an essential feature of T2DM, so achieving normal blood glucose levels is the main goal
of T2DM treatment.

Glucagon-like peptide 1 (GLP-1) is an intestinal hormone that plays an important role
in regulating blood sugar, promoting insulin secretion in a glucose-dependent manner, and inhibiting gastric emptying and food intake 。 In recent years, GLP-1 analogues and drugs to prevent GLP-1 degradation have been used in the treatment of T2DM, so in-depth exploration of the endogenous release mechanism of GLP-1 and the regulation mechanism of glucose homeostasis will help provide a new theoretical basis and target for the diagnosis and treatment of T2DM
.

The main active forms of thyroid hormone (TH) include T3 and T4, of which T3 is the most active, and its biological function is mainly mediated
by TH receptors (TR).
TR belongs to the nuclear receptor superfamily and is a ligand (T3)-dependent transcription factor, with α and β subtypes, of which TRα is highly expressed in tissues such as heart, bone, muscle and fat, while TRβ is mainly expressed in tissues
such as liver, kidney, and pituitary.
The thyroid gland has a significant effect on glucose metabolism, but the underlying mechanism of action is uncertain
because the effects of thyroid hormones on glucose tolerance and insulin sensitivity in different tissues may have different effects on the body's blood glucose levels.

On October 27, 2022, Ying Hao's research group at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences published an online publication in the journal Nature Communications entitled : Hepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism
.

The study found that thyroid hormones are able to link with
blood glucose homeostasis through GLP-1.
Activating the hepatic thyroid hormone signaling pathway has the effect of insulin secretion and lowering blood sugar, the mode of action is to change the composition of bile acids by inhibiting the expression of CYP8B1, increase the level of non-12α-hydroxybile acids with FXR antagonism, thereby increasing the production of GLP-1 by inhibiting the intestinal FXR signaling pathway, revealing the feasibility
of TRβ agonists targeting the liver in the future for the treatment of type 2 diabetes.

The study found that the active form of thyroid hormone (TH), triiodothyronine (T3), significantly promoted GLP-1 and insulin secretion, thereby improving blood glucose homeostasis
in hypothyroidism model mice.
The use of GLP-1 receptor antagonists can inhibit the effect of T3 in promoting insulin secretion and lowering blood sugar, indicating that the regulation of T3 for blood glucose homeostasis depends on GLP-1
.

This study further utilized a transgenic mouse model of liver tissue-specific knockout of thyroid hormone receptor β (TRβ) and a selective agonist of TRβ targeting the liver, and found that the TH signaling pathway mediated by liver TRβ is indispensable for T3 to regulate GLP-1 and insulin secretion and T3 to lower blood sugar
.
Similarly, in diet-induced obese mouse models, liver-targeting TRβ-selective agonists were equally able to raise insulin and GLP-1 levels and lower blood sugar
.
In terms of molecular mechanism, T3 changes the composition of bile acids by inhibiting the expression level of CYP8B1 in the liver, 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.

The role of hepatic thyroid hormone signaling pathways in regulating blood glucose homeostasis

The study also found a physiological correlation
between T3 levels and levels of GLP-1 levels and bile acids with FXR antagonism in people with normal thyroid function.
The study shows the importance of thyroid hormone in maintaining blood glucose homeostasis, reveals a new mechanism by which the liver TH-TRβ signaling pathway regulates GLP-1 production through bile acid-mediated FXR antagonism, and will lay a theoretical foundation
for the development of new therapies for T2DM and related metabolic diseases.

Yan Ying, a doctoral candidate at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, is the first author of the paper, and Ying Hao, a researcher at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, and Jiang Jingjing, deputy chief physician of Zhongshan Hospital, the Affiliated Hospital of Fudan University, are the corresponding authors
of this paper 。 The research was supported by the National Natural Science Foundation of China and the Key Research Program of the Major Research Program on Spatiotemporal Network Regulation of Glucose and Lipid Metabolism, and also supported by Jiang Changtao, a researcher from the School of Basic Medicine of Peking University, Professor Fang Zhongze of Tianjin Medical University, a researcher Xie Cen from the Shanghai Institute of Materia Medica, and a researcher Wang Jiqiu from Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, and a public technology platform and animal platform of the Shanghai Institute of Nutrition and Health
, Chinese Academy of Sciences.

Links to papers:

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