<br>GLP-1 和 GIP 受体通过不同的 β-arrestin 2 依赖性途径发出信号来调节胰腺 β 细胞功能,Cell Reports

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GLP-1 和 GIP 受体通过不同的 β-arrestin 2 依赖性途径发出信号来调节胰腺 β 细胞功能
Cell Reports ( IF 7.5 ) Pub Date : 2023-10-31 , DOI: 10.1016/j.celrep.2023.113326
Nour Zaïmia ₁ , Joelle Obeid ₁ , Annie Varrault ₁ , Julia Sabatier ₂ , Christophe Broca ₂ , Patrick Gilon ₃ , Safia Costes ₁ , Gyslaine Bertrand ₁ , Magalie A Ravier ₁

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胰高血糖素样肽 1 (GLP-1R) 和葡萄糖依赖性促胰岛素多肽 (GIPR) 受体是参与葡萄糖稳态的 G 蛋白偶联受体。糖尿病条件会降低人类胰岛中的 β-arrestin 2 (ARRB2) 水平。在小鼠 β 细胞中，ARRB2 在生理剂量的 GLP-1 下通过部分解偶联环 AMP (cAMP)/蛋白激酶 A (PKA) 信号来抑制胰岛素分泌，而在药理学剂量下，ARRB2 会激活细胞外信号相关激酶 (ERK)/ cAMP 反应元件结合蛋白 (CREB) 需要 ARRB2。相比之下，小鼠和人类胰岛中 GIP 增强的胰岛素分泌需要 ARRB2。 GIPR-ARRB2 轴不参与 cAMP/PKA 或 ERK 信号传导，但介导 GIP 诱导的 F-肌动蛋白解聚。最后，双重 GLP-1/GIP 激动剂替泽帕肽不需要 ARRB2 来增强胰岛素分泌。因此，ARRB2 在调节 GLP-1R 和 GIPR 信号传导中发挥着独特的作用，我们强调 (1) 它在生理环境中的作用以及它在糖尿病等病理情况下表达减少可能产生的功能后果，以及 (2) 评估的重要性激动剂（偏向/双重）用于治疗目的的信号传导途径。

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GLP-1 and GIP receptors signal through distinct β-arrestin 2-dependent pathways to regulate pancreatic β cell function

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.

更新日期：2023-10-31

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