小柯机器人

美国礼来公司Anish Konkar、德国赛诺菲公司Martin Bossart等研究人员合作揭示一种单分子多肽GLP-1/GIP/GCG受体三活性激动剂对减肥和血糖控制的影响。相关论文于2021年12月20日在线发表在《细胞—代谢》杂志上。

研究人员表示，结合了胰高血糖素样肽-1（GLP-1）、葡萄糖依赖性胰岛素多肽（GIP）和胰高血糖素（GCG）活性的单分子三联肠促胰岛素，已经在啮齿动物模型中证明了体重的减轻和血糖控制的改善。

研究人员开发了SAR441255，一种合成的GLP-1、GCG和GIP受体的多肽激动剂，结构上以exendin-4序列为基础。SAR441255显示出高效力，平衡地激活了所有三个靶标受体。在动物模型中，代谢结果优于GLP-1/GCG双重受体激动剂的结果。临床前体内正电子发射断层成像显示SAR441255与GLP-1和GCG受体结合。在健康受试者中，SAR441255改善了混合膳食耐受性试验中的血糖控制，并影响了GCG和GIP受体激活的生物标志物。单剂量的SAR441255耐受性良好。这些结果表明，将GIP活性整合到GLP-1和GCG受体双重激动中，可改善减肥和血糖控制的效果，同时缓冲慢性GCG受体激动的致糖尿病风险。

附：英文原文

Title: Effects on weight loss and glycemic control with SAR441255, a potent unimolecular peptide GLP-1/GIP/GCG receptor triagonist

Author: Martin Bossart, Michael Wagner, Ralf Elvert, Andreas Evers, Thomas Hübschle, Tim Kloeckener, Katrin Lorenz, Christine Moessinger, Olof Eriksson, Irina Velikyan, Stefan Pierrou, Lars Johansson, Gabriele Dietert, Yasmin Dietz-Baum, Thomas Kissner, Irene Nowotny, Christine Einig, Christelle Jan, Faiza Rharbaoui, Johann Gassenhuber, Hans-Peter Prochnow, Inoncent Agueusop, Niels Porksen, William B. Smith, Almut Nitsche, Anish Konkar

Issue&Volume: 2021-12-20

Abstract: Unimolecular triple incretins, combining the activity of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have demonstrated reduction in body weight and improved glucose control in rodent models. We developed SAR441255, a synthetic peptide agonist of the GLP-1, GCG, and GIP receptors, structurally based on the exendin-4 sequence. SAR441255 displays high potency with balanced activation of all three target receptors. In animal models, metabolic outcomes were superior to results with a dual GLP-1/GCG receptor agonist. Preclinical in vivo positron emission tomography imaging demonstrated SAR441255 binding to GLP-1 and GCG receptors. In healthy subjects, SAR441255 improved glycemic control during a mixed-meal tolerance test and impacted biomarkers for GCG and GIP receptor activation. Single doses of SAR441255 were well tolerated. The results demonstrate that integrating GIP activity into dual GLP-1 and GCG receptor agonism provides improved effects on weight loss and glycemic control while buffering the diabetogenic risk of chronic GCG receptor agonism.

DOI: 10.1016/j.cmet.2021.12.005

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00624-0

Cell Metabolism：《细胞—代谢》，创刊于2005年。隶属于细胞出版社，最新IF：31.373
官方网址：https://www.cell.com/cell-metabolism/home
投稿链接：https://www.editorialmanager.com/cell-metabolism/default.aspx