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一种双重 GLP-1/GIP 受体激动剂不会在其受体上拮抗胰高血糖素，而是可能在 GLP-1 受体上作为一种偏向激动剂发挥作用。

A Dual GLP-1/GIP Receptor Agonist Does Not Antagonize Glucagon at Its Receptor but May Act as a Biased Agonist at the GLP-1 Receptor.

机构信息

Department of Pharmacology & Toxicology, Faculty of Medicine, Kuwait University, PO Box 24923, 13110 Safat, Kuwait.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, PO Box 24923, 13110 Safat, Kuwait.

出版信息

Int J Mol Sci. 2019 Jul 19;20(14):3532. doi: 10.3390/ijms20143532.

DOI:10.3390/ijms20143532
PMID:31330984
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6678630/
Abstract

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important regulators of metabolism, making their receptors (GLP-1R and GIPR) attractive targets in the treatment of type 2 diabetes mellitus (T2DM). GLP-1R agonists are used clinically to treat T2DM but the use of GIPR agonists remains controversial. Recent studies suggest that simultaneous activation of GLP-1R and GIPR with a single peptide provides superior glycemic control with fewer adverse effects than activation of GLP-1R alone. We investigated the signaling properties of a recently reported dual-incretin receptor agonist (P18). GLP-1R, GIPR, and the closely related glucagon receptor (GCGR) were expressed in HEK-293 cells. Activation of adenylate cyclase via Gα was monitored using a luciferase-linked reporter gene (CRE-Luc) assay. Arrestin recruitment was monitored using a bioluminescence resonance energy transfer (BRET) assay. GLP-1, GIP, and glucagon displayed exquisite selectivity for their receptors in the CRE-Luc assay. P18 activated GLP-1R with similar potency to GLP-1 and GIPR with higher potency than GIP. Interestingly, P18 was less effective than GLP-1 at recruiting arrestin to GLP-1R and was inactive at GCGR. These data suggest that P18 can act as both a dual-incretin receptor agonist, and as a G protein-biased agonist at GLP-1R.

摘要

胰高血糖素样肽-1（GLP-1）和葡萄糖依赖性胰岛素释放肽（GIP）是代谢的重要调节剂，使其受体（GLP-1R 和 GIPR）成为 2 型糖尿病（T2DM）治疗的有吸引力的靶点。GLP-1R 激动剂临床上用于治疗 T2DM，但 GIPR 激动剂的使用仍存在争议。最近的研究表明，用单一肽同时激活 GLP-1R 和 GIPR 可提供优于单独激活 GLP-1R 的血糖控制，且不良反应更少。我们研究了最近报道的双重肠降血糖素受体激动剂（P18）的信号转导特性。GLP-1R、GIPR 和密切相关的胰高血糖素受体（GCGR）在 HEK-293 细胞中表达。通过 Gα 激活腺苷酸环化酶，使用荧光素酶连接报告基因（CRE-Luc）测定法进行监测。使用生物发光共振能量转移（BRET）测定法监测衔接蛋白募集。GLP-1、GIP 和胰高血糖素在 CRE-Luc 测定法中对其受体表现出极高的选择性。P18 对 GLP-1R 的激活与 GLP-1 和 GIPR 的激活具有相似的效力，而对 GIPR 的激活效力高于 GIP。有趣的是，与 GLP-1 相比，P18 募集 GLP-1R 衔接蛋白的效率较低，并且对 GCGR 无活性。这些数据表明，P18 可以作为双重肠降血糖素受体激动剂，以及 GLP-1R 的 G 蛋白偏向激动剂。

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