Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models
文献类型：期刊论文
| 作者 | Guo, Dan-yang; Li, De-wen; Ning, Meng-meng ; Dang, Xiang-yu; Zhang, Li-na; Zeng, Li-min; Hu, You-hong; Leng, Ying
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| 刊名 | BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
 |
| 出版日期 | 2015-10-30 |
| 卷号 | 466期号:4页码:740-747 |
| 关键词 | Yhhu4488 GPR40 Type 2 diabetes mellitus Glucagon-like peptide-1 Insulin |
| ISSN号 | 0006-291X |
| DOI | 10.1016/j.bbrc.2015.09.130 |
| 文献子类 | Article |
| 英文摘要 | G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic beta-cells and activated by long-chain fatty acids. GPR40 has drawn considerable interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in glucagon-like peptide-1 (GLP-1)producing enteroendocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti-diabetic efficacy. In the present study, we discovered a novel GPR40 agonist, yhhu4488, which is structurally different from other reported GPR40 agonists. Yhhu4488 showed potent agonist activity with EC50 of 49.96 nM, 70.83 nM and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells (FRIC) via triggering endogenous calcium store mobilization and extracellular calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. Chronic administration of yhhu4488 effectively decreased fasting blood glucose level, improved beta-cell function and lipid homeostasis in type 2 diabetic ob/ob mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 secretion, improves metabolic control and beta-cell function, suggesting its promising potential for the treatment of type 2 diabetes. (C) 2015 Elsevier Inc. All rights reserved. |
| WOS关键词 | GLUCAGON-LIKE PEPTIDE-1 ; PANCREATIC BETA-CELLS ; TYPE-2 DIABETES-MELLITUS ; INSULIN-SECRETION ; FATTY-ACIDS ; RECEPTOR ; DISCOVERY ; TAK-875 |
| 资助项目 | [CASIMM0120152028] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Biophysics |
| 语种 | 英语 |
| WOS记录号 | WOS:000363601600021 |
| 出版者 | ACADEMIC PRESS INC ELSEVIER SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276350]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药理学第一研究室 |
| 通讯作者 | Leng, Ying |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Guo, Dan-yang,Li, De-wen,Ning, Meng-meng,et al. Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models[J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,2015,466(4):740-747. |
| APA | Guo, Dan-yang.,Li, De-wen.,Ning, Meng-meng.,Dang, Xiang-yu.,Zhang, Li-na.,...&Leng, Ying.(2015).Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models.BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS,466(4),740-747. |
| MLA | Guo, Dan-yang,et al."Yhhu4488, a novel GPR40 agonist, promotes GLP-1 secretion and exerts anti-diabetic effect in rodent models".BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 466.4(2015):740-747. |
入库方式： OAI收割
来源：上海药物研究所
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