Type 2 diabetes (T2D) mellitus has emerged as a major global health concern that has accelerated in recent years due to poor diet and lifestyle. Afflicted individuals have high blood glucose levels that stem from the inability of the pancreas to make enough insulin to meet demand. Although medication can help to maintain normal blood glucose levels in individuals with chronic disease, many of these medicines are outdated, have severe side effects, and often become less efficacious over time, necessitating the need for insulin therapy. G protein–coupled receptors (GPCRs) regulate many physiologic processes, including blood glucose levels. In pancreatic β cells, GPCRs regulate β-cell growth, apoptosis, and insulin secretion, which are all critical in maintaining sufficient β-cell mass and insulin output to ensure euglycemia. In recent years, new insights into the signaling of incretin receptors and other GPCRs have underscored the potential of these receptors as desirable targets in the treatment of diabetes. The signaling of these receptors is modulated by GPCR kinases (GRKs) that phosphorylate agonist-activated GPCRs, marking the receptor for arrestin binding and internalization. Interestingly, genome-wide association studies using diabetic patient cohorts link the GRKs and arrestins with T2D. Moreover, recent reports show that GRKs and arrestins expressed in the β cell serve a critical role in the regulation of β-cell function, including β-cell growth and insulin secretion in both GPCR-dependent and -independent pathways. In this review, we describe recent insights into GPCR signaling and the importance of GRK function in modulating β-cell physiology.

Pancreatic β cells contain a diverse array of G protein–coupled receptors (GPCRs) that have been shown to improve β-cell function and survival, yet only a handful have been successfully targeted in the treatment of diabetes. This review discusses recent advances in our understanding of β-cell GPCR pharmacology and regulation by GPCR kinases while also highlighting the necessity of investigating islet-enriched GPCRs that have largely been unexplored to unveil novel treatment strategies.

2 型糖尿病 (T2D) 已成为全球主要的健康问题，近年来由于不良的饮食和生活方式而加剧。患者的血糖水平较高，这是由于胰腺无法产生足够的胰岛素来满足需求。虽然药物可以帮助慢性病患者维持正常的血糖水平，但其中许多药物已经过时，具有严重的副作用，并且通常随着时间的推移而变得不那么有效，因此需要胰岛素治疗。 G 蛋白偶联受体 (GPCR) 调节许多生理过程，包括血糖水平。在胰腺β细胞中，GPCR 调节β细胞生长、凋亡和胰岛素分泌，这些对于维持足够的β细胞质量和胰岛素输出以确保血糖正常至关重要。近年来，对肠促胰岛素受体和其他 GPCR 信号传导的新见解强调了这些受体作为糖尿病治疗理想靶点的潜力。这些受体的信号传导受到 GPCR 激酶 (GRK) 的调节，GPCR 激酶 (GRK) 会磷酸化激动剂激活的 GPCR，从而标记受体以进行抑制蛋白结合和内化。有趣的是，使用糖尿病患者队列进行的全基因组关联研究将 GRK 和抑制蛋白与 T2D 联系起来。此外，最近的报告表明，在β细胞中表达的 GRK 和抑制蛋白在调节β细胞功能中发挥着关键作用，包括在 GPCR 依赖性和非依赖性途径中的β细胞生长和胰岛素分泌。在这篇综述中，我们描述了对 GPCR 信号传导的最新见解以及 GRK 功能在调节β细胞生理学中的重要性。

胰腺β细胞含有多种 G 蛋白偶联受体 (GPCR)，这些受体已被证明可以改善β细胞功能和存活率，但只有少数几种已成功用于治疗糖尿病。这篇综述讨论了我们对β细胞 GPCR 药理学和 GPCR 激酶调节的理解的最新进展，同时也强调了研究富含胰岛的 GPCR 的必要性，这些 GPCR 在很大程度上尚未被探索，以揭示新的治疗策略。