TGR5 agonist ameliorates insulin resistance in skeletal muscles and improves glucose homeostasis in diabetic mice

doi:10.1016/j.metabol.2019.07.003

	TGR5 agonist ameliorates insulin resistance in skeletal muscles and improves glucose homeostasis in diabetic mice
	Huang, Suling; Ma, Shanyao; Ning, Mengmeng; Yang, Wenji; Ye, Yangliang; Zhang, Lina; Shen, Jianhua; Leng, Ying
刊名	METABOLISM-CLINICAL AND EXPERIMENTAL
	2019-10-01
卷号	99 页码:45-56
关键词	TGR5 Glucose homeostasis Insulin resistance Skeletal muscle Type 2 diabetes
ISSN号	0026-0495
DOI	10.1016/j.metabol.2019.07.003
通讯作者	Shen, Jianhua(jhshen@simm.ac.cn) ; Leng, Ying(yleng@simm.ac.cn)
英文摘要	Background and purpose: TGR5 plays an important role in many physiological processes. However, the functions of TGR5 in the regulation of the glucose metabolism and insulin sensitivity in the skeletal muscles have not been fully elucidated. We synthesized MN6 as a potent and selective TGR5 agonist. Here, the effect of MN6 on insulin resistance in skeletal muscles was evaluated in diet-induced obese (DIO) mice and C2C12 myotubes, and the underlying mechanisms were explored. Methods: The activation of MN6 on human and mouse TGR5 was evaluated by a cAMP assay in HEK293 cell lines stable expressing hTGR5/CRE or mTGR5/CRE cells. GLP-1 secretion was measured in NCI-H716 cells and CD1 mice. The acute and chronic effects of MN6 on regulating metabolic abnormalities were observed in ob/ob and DIO mice. 2-deoxyglucose uptake was examined in isolated skeletal muscles. Akt phosphorylation, glucose uptake and glycogen synthesis were examined to assess the effects of MN6 on palmitate-induced insulin resistance in C2C12 myotubes. Results: MN6 potently activated human and mouse TGR5 with EC50 values of 15.9 and 17.9 nmol/L, respectively, and stimulated GLP-1 secretion in NCI-H716 cells and CD1 mice. A single oral dose of MN6 significantly decreased the blood glucose levels in ob/ob mice. Treatment with MN6 for 15 days reduced the fasting blood glucose and HbA1c levels in ob/ob mice. MN6 improved glucose and insulin tolerance and enhanced the insulin-stimulated glucose uptake of skeletal muscles in DIO mice. The palmitate-induced impairment of insulin-stimulated Akt phosphorylation, glucose uptake and glycogen synthesis in C2C12 myotubes could be prevented by MN6. The effect of MN6 on palmitate-impaired insulin-stimulated Akt phosphorylation was abolished by siRNA-mediated knockdown of TGR5 or by the inhibition of adenylate cyclase or protein kinase A, suggesting that this effect is dependent on the activation of TGR5 and the cAMP/PKA pathway. Conclusions: Our study identified that a TGR5 agonist could ameliorate insulin resistance by the cAMP/PKA pathway in skeletal muscles; this uncovered a new effect of the TGR5 agonist on regulating the glucose metabolism and insulin sensitivity in skeletal muscles and further strengthened its potential value for the treatment of type 2 diabetes. (C) 2019 Elsevier Inc. All rights reserved.
资助项目	National Natural Science Foundation of China[81202571]
WOS关键词	PROTEIN-KINASE ; BILE-ACIDS ; BIOLOGICAL EVALUATION ; ENERGY-EXPENDITURE ; RECEPTOR ; POTENT ; DERIVATIVES ; MECHANISMS ; INHIBITION ; C57BL/6J
WOS研究方向	Endocrinology & Metabolism
语种	英语
出版者	W B SAUNDERS CO-ELSEVIER INC
WOS记录号	WOS:000493795800007
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281882]
专题	中国科学院上海药物研究所
通讯作者	Shen, Jianhua; Leng, Ying
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Huang, Suling,Ma, Shanyao,Ning, Mengmeng,et al. TGR5 agonist ameliorates insulin resistance in skeletal muscles and improves glucose homeostasis in diabetic mice[J]. METABOLISM-CLINICAL AND EXPERIMENTAL,2019,99:45-56.
APA	Huang, Suling.,Ma, Shanyao.,Ning, Mengmeng.,Yang, Wenji.,Ye, Yangliang.,...&Leng, Ying.(2019).TGR5 agonist ameliorates insulin resistance in skeletal muscles and improves glucose homeostasis in diabetic mice.METABOLISM-CLINICAL AND EXPERIMENTAL,99,45-56.
MLA	Huang, Suling,et al."TGR5 agonist ameliorates insulin resistance in skeletal muscles and improves glucose homeostasis in diabetic mice".METABOLISM-CLINICAL AND EXPERIMENTAL 99(2019):45-56.