肠促胰岛素
受体
胰高血糖素样肽1受体
兴奋剂
胃抑制多肽
下调和上调
胰高血糖素样肽-1
激素
内分泌学
内科学
G蛋白偶联受体
药理学
糖尿病
化学
医学
胰高血糖素
2型糖尿病
生物化学
基因
作者
Lærke S. Gasbjerg,Mette M. Rosenkilde,Juris J. Meier,Jens J. Holst,Filip K. Knop
摘要
Abstract Tirzepatide is a unimolecular co‐agonist of the glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor‐activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP‐1 and GIP, their receptors, and previous results of co‐targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP‐1 and GIP receptor activation, tirzepatide does not seem to have a classical co‐activating mode of action in humans. Rather, in vitro studies of the human GLP‐1 and GIP receptors reveal a biased GLP‐1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.
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