Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes¹. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide² and AMG-133 (ref. ³) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

基于肠促胰岛素的疗法在对抗肥胖和 2 型糖尿病方面非常成功¹ 。然而，葡萄糖依赖性促胰岛素多肽 (GIP) 受体 (GIPR) 的激活和抑制与胰高血糖素样肽 1 (GLP-1) 受体 (GLP-1R) 的激活相结合，都导致了类似的临床结果，如GIPR-GLP-1R 共激动剂替泽帕肽²和 AMG-133（参考文献³ ）结合了 GIPR 拮抗作用和 GLP-1R 激动作用。这强调了更好地了解 GIP 系统的重要性。在这里，我们通过将 47 种GIPR变体的体外药理学特征与临床表型的负荷测试和体内研究相结合，展示了 GIPR 功能招募 β-arrestin 的必要性。对具有不同配体结合能力、Gs 激活（环磷酸腺苷生成）和 β-arrestin 2 募集和内化的变体的负荷测试表明，与仅在 Gs 信号传导中受损的变体不同，Gs 和 β-arrestin 2 募集均受损的变体有助于较低的肥胖相关特征。内体 Gs 介导的变体信号显示出 β-arrestin 依赖性，并且 β-arrestin 2 的基因消除会损害环单磷酸腺苷的产生并降低 GIP 对雄性小鼠血糖控制的功效。这项研究强调了 β-抑制蛋白在调节 GIPR 信号传导和生物活性整体保留方面的重要影响，这可能促进 GIPR 系统治疗靶向的新发展。