Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon (GCG) are important regulators of insulin secretion and energy metabolism. Here we sought to investigate how signal bias between cyclic AMP and -arrestin-2 recruitment can modulate the effects of prolonged agonist stimulation at each of these receptors. We generated analogues of GLP-1, GCG and GIP which in some cases showed selective reduction in -arrestin-2 recruitment versus cAMP signalling compared to the parent peptide. Despite reduced acute signalling potency and/or efficacy, some biased GLP-1 and GIP analogues increased maximal sustained insulin secretion, although only at high agonist concentrations. Biased GCG analogues did not affect maximal insulin release from beta cells, or glucose output in hepatocytes.

中文翻译：

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胰高血糖素家族受体的信号偏倚：基本原理和下游影响

肽激素胰高血糖素样肽1（GLP-1），葡萄糖依赖性促胰岛素多肽（GIP）和胰高血糖素（GCG）的受体是胰岛素分泌和能量代谢的重要调节剂。在这里，我们试图研究环状AMP和-arrestin-2募集之间的信号偏向如何调节这些受体中每一个受体的激动剂刺激的延长。我们生成了GLP-1，GCG和GIP的类似物，与母体肽相比，在某些情况下，它们与cAMP信号传导相比，选择性抑制了-arrestin-2募集。尽管降低了急性信号强度和/或功效，但某些偏倚的GLP-1和GIP类似物增加了最大的持续胰岛素分泌，尽管仅在高激动剂浓度下。偏置的GCG类似物不会影响β细胞的最大胰岛素释放或肝细胞中的葡萄糖输出。