IGF, Université Montpellier, CNRS, INSERM, Montpellier, France.
LTCD, IRMB, CHU Montpellier, Montpellier, France.
Cell Rep. 2023 Nov 28;42(11):113326. doi: 10.1016/j.celrep.2023.113326. Epub 2023 Oct 31.
Glucagon-like peptide 1 (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIPR) receptors are G-protein-coupled receptors involved in glucose homeostasis. Diabetogenic conditions decrease β-arrestin 2 (ARRB2) levels in human islets. In mouse β cells, ARRB2 dampens insulin secretion by partially uncoupling cyclic AMP (cAMP)/protein kinase A (PKA) signaling at physiological doses of GLP-1, whereas at pharmacological doses, the activation of extracellular signal-related kinase (ERK)/cAMP-responsive element-binding protein (CREB) requires ARRB2. In contrast, GIP-potentiated insulin secretion needs ARRB2 in mouse and human islets. The GIPR-ARRB2 axis is not involved in cAMP/PKA or ERK signaling but does mediate GIP-induced F-actin depolymerization. Finally, the dual GLP-1/GIP agonist tirzepatide does not require ARRB2 for the potentiation of insulin secretion. Thus, ARRB2 plays distinct roles in regulating GLP-1R and GIPR signaling, and we highlight (1) its role in the physiological context and the possible functional consequences of its decreased expression in pathological situations such as diabetes and (2) the importance of assessing the signaling pathways engaged by the agonists (biased/dual) for therapeutic purposes.
胰高血糖素样肽 1（GLP-1R）和葡萄糖依赖性胰岛素促分泌多肽（GIPR）受体是参与葡萄糖稳态的 G 蛋白偶联受体。致糖尿病条件会降低人胰岛中的β-arrestin 2（ARRB2）水平。在小鼠β细胞中，ARRB2 通过部分解偶联环磷酸腺苷（cAMP）/蛋白激酶 A（PKA）信号来抑制胰岛素分泌，在生理剂量的 GLP-1 下，而在药理剂量下，细胞外信号相关激酶（ERK）/cAMP 反应元件结合蛋白（CREB）的激活需要 ARRB2。相比之下，GIP 增强的胰岛素分泌需要在小鼠和人胰岛中 ARRB2。GIPR-ARRB2 轴不参与 cAMP/PKA 或 ERK 信号，但确实介导 GIP 诱导的 F-肌动蛋白解聚。最后，双重 GLP-1/GIP 激动剂替西帕肽增强胰岛素分泌不需要 ARRB2。因此，ARRB2 在调节 GLP-1R 和 GIPR 信号中发挥不同的作用，我们强调 (1) 其在生理情况下的作用及其在糖尿病等病理情况下表达降低的可能功能后果，以及 (2) 评估激动剂（偏向/双重）参与的信号通路对于治疗目的的重要性。
