1] Institute for Diabetes and Obesity, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. [2] Department of Medicine, Division of Metabolic Diseases,Technische Universität München, Munich, Germany. [3] Department of Chemistry, Indiana University, Bloomington, Indiana, USA.
1] Department of Chemistry, Indiana University, Bloomington, Indiana, USA. [2] Marcadia Biotech, Carmel, Indiana, USA.
Nat Med. 2015 Jan;21(1):27-36. doi: 10.1038/nm.3761. Epub 2014 Dec 8.
We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.
我们报告了一种新的单体肽的发现，该肽通过作为三种关键代谢相关肽激素受体（胰高血糖素样肽-1（GLP-1）、葡萄糖依赖性胰岛素释放肽（GIP）和胰高血糖素受体）的激动剂，在肥胖症的啮齿动物模型中减轻体重和糖尿病并发症。这种三激动剂在每个受体上均表现出超生理效力和同等的组成活性，而与其他相关受体无交叉反应。这种平衡的单分子三激动作用被证明优于任何现有的双重共激动剂和同类最佳的单激动剂，可降低体重、增强血糖控制并逆转相关啮齿动物模型中的肝脂肪变性。各种功能丧失模型，包括基因敲除、药理学阻断和选择性化学敲除，证实了体内每种组成活性的作用。我们证明，这些单个组成活性协同调节整体代谢功效，主要归因于协同的胰高血糖素作用以增加能量消耗、GLP-1 作用以减少热量摄入和改善葡萄糖控制，以及 GIP 作用以增强肠促胰岛素效应并缓冲内在胰高血糖素活性的致糖尿病作用。这些临床前研究表明，到目前为止，这种单分子、多药物策略有可能成为逆转肥胖和相关代谢紊乱的最有效药物治疗方法。
