Abstract：
Surprisingly, agonists, as well as antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR), are currently being used or investigated as treatment options for type 2 diabetes and obesity - and both, when combined with glucagon-like peptide 1 receptor (GLP-1R) agonism, enhance GLP-1-induced glycemia and weight loss further. This paradox raises several questions regarding not only the mechanisms of actions of GIP but also the processes engaged during the activation of both the GIP and GLP-1 receptors. Here, we provide an overview of studies of the properties and actions of peptide-derived GIPR antagonists, focusing on GIP(3-30)NH2, a naturally occurring N- and C-terminal truncation of GIP(1-42). GIP(3-30)NH2 was the first GIPR antagonist administered to humans. GIP(3-30)NH2 and a few additional antagonists, like Pro3-GIP, have been used in both in vitro and in vivo studies to elucidate the molecular and cellular consequences of GIPR inhibition, desensitization, and internalization and, at a larger scale, the role of the GIP system in health and disease. We provide an overview of these studies combined with recent knowledge regarding the effects of naturally occurring variants of the GIPR system and species differences within the GIP system to enhance our understanding of the GIPR as a drug target.
摘要：
令人惊讶的是,激动剂,以及葡萄糖依赖性促胰岛素多肽受体（GIPR）的拮抗剂，目前正被用作或研究2型糖尿病和肥胖症的治疗方案，当与胰高血糖素样肽1受体（GLP-1R）激动结合时，进一步增强GLP-1诱导的血糖和体重减轻。这个悖论提出了几个问题，不仅涉及GIP的作用机制，而且涉及GIP和GLP-1受体激活过程中的过程。这里,我们概述了肽衍生的GIPR拮抗剂的性质和作用的研究，集中于GIP(3-30)NH2,GIP(1-42)的天然存在的N-和C-末端截短。GIP(3-30)NH2是向人类施用的第一个GIPR拮抗剂。GIP（3-30）NH2和一些其他拮抗剂，比如Pro3-GIP,已用于体外和体内研究，以阐明GIPR抑制的分子和细胞后果，脱敏,和内部化，在更大的范围内，GIP系统在健康和疾病中的作用。我们提供了这些研究的概述，并结合了有关GIPR系统的天然变体和GIP系统内物种差异的最新知识，以增强我们对GIPR作为药物靶标的理解。
