TGR5 agonist ameliorates insulin resistance in skeletal muscles and improves glucose homeostasis in diabetic mice
文献类型：期刊论文
| 作者 | Huang, Suling ; Ma, Shanyao; Ning, Mengmeng; Yang, Wenji; Ye, Yangliang; Zhang, Lina; Shen, Jianhua; Leng, Ying
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| 刊名 | METABOLISM-CLINICAL AND EXPERIMENTAL
 |
| 出版日期 | 2019-10-01 |
| 卷号 | 99页码:45-56 |
| ISSN号 | 0026-0495 |
| 关键词 | TGR5 Glucose homeostasis Insulin resistance Skeletal muscle Type 2 diabetes |
| 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. |
| WOS关键词 | PROTEIN-KINASE ; BILE-ACIDS ; BIOLOGICAL EVALUATION ; ENERGY-EXPENDITURE ; RECEPTOR ; POTENT ; DERIVATIVES ; MECHANISMS ; INHIBITION ; C57BL/6J |
| 资助项目 | National Natural Science Foundation of China[81202571] |
| 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 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/281882]  |
| 专题 | 新药研究国家重点实验室 |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
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