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MS-275，一种 1 类组蛋白去乙酰化酶抑制剂，增强胰高血糖素样肽-1 受体激动剂作用，改善血糖控制，减少饮食诱导肥胖小鼠的肥胖。

MS-275, a class 1 histone deacetylase inhibitor augments glucagon-like peptide-1 receptor agonism to improve glycemic control and reduce obesity in diet-induced obese mice.

机构信息

Dr. Reddy's Institute of Life Sciences University of Hyderabad Campus, Hyderabad, India.

Manipal Academy of Higher Education, Manipal, India.

出版信息

Elife. 2020 Dec 22;9:e52212. doi: 10.7554/eLife.52212.

DOI:10.7554/eLife.52212
PMID:33349332
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7755393/
Abstract

Given its glycemic efficacy and ability to reduce the body weight, glucagon-like peptide 1 receptor (GLP-1R) agonism has emerged as a preferred treatment for diabetes associated with obesity. We here report that a small-molecule Class 1 histone deacetylase (HDAC) inhibitor Entinostat (MS-275) enhances GLP-1R agonism to potentiate glucose-stimulated insulin secretion and decrease body weight in diet-induced obese (DIO) mice. MS-275 is not an agonist or allosteric activator of GLP-1R but enhances the sustained receptor-mediated signaling through the modulation of the expression of proteins involved in the signaling pathway. MS-275 and liraglutide combined therapy improved fasting glycemia upon short-term treatment and a chronic administration causes a reduction of obesity in DIO mice. Overall, our results emphasize the therapeutic potential of MS-275 as an adjunct to GLP-1R therapy in the treatment of diabetes and obesity.

摘要

鉴于其降血糖功效和减轻体重的能力，胰高血糖素样肽 1 受体 (GLP-1R) 激动剂已成为治疗肥胖相关糖尿病的首选方法。我们在此报告，一种小分子 Class 1 组蛋白去乙酰化酶 (HDAC) 抑制剂 Entinostat（MS-275）可增强 GLP-1R 激动作用，从而增强葡萄糖刺激的胰岛素分泌并减轻饮食诱导肥胖 (DIO) 小鼠的体重。MS-275 不是 GLP-1R 的激动剂或别构激活剂，而是通过调节信号通路中涉及的蛋白质的表达来增强持续的受体介导的信号转导。MS-275 和利拉鲁肽联合治疗可改善短期治疗时的空腹血糖，而长期给药可减少 DIO 小鼠的肥胖。总体而言，我们的研究结果强调了 MS-275 作为 GLP-1R 治疗辅助药物在治疗糖尿病和肥胖症方面的治疗潜力。

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