G蛋白偶联受体和受体激酶在胰腺β细胞功能和糖尿病中的作用

IF 19.3 1区 医学 Q1 PHARMACOLOGY & PHARMACY Pharmacological Reviews Pub Date : 2024-02-13 DOI:10.1124/pharmrev.123.001015
Matthew J Varney, Jeffrey L Benovic
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引用次数: 0

摘要

2 型糖尿病(T2D)已成为全球关注的主要健康问题,近年来,由于不良的饮食和生活方式,该病的发病率加速上升。由于胰腺无法制造足够的胰岛素来满足需求,患者的血糖水平很高。虽然药物可以帮助慢性病患者维持正常的血糖水平,但许多药物已经过时,有严重的副作用,而且随着时间的推移,疗效往往会降低,因此必须使用胰岛素治疗。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,GPCRs调节β细胞的生长、凋亡和胰岛素分泌,这对于维持足够的β细胞质量和胰岛素输出以确保优生至关重要。近年来,对增量素受体和其他 GPCR 信号传导的新认识凸显了这些受体作为治疗糖尿病理想靶点的潜力。这些受体的信号传导受 GPCR 激酶(GRKs)的调节,GRKs 可使激动剂激活的 GPCRs 磷酸化,从而使受体与抑制素结合并内化。有趣的是,利用糖尿病患者队列进行的全基因组关联研究将 GRKs 和 arrestin 与 T2D 联系起来。此外,最近的报告显示,β 细胞中表达的 GRKs 和 arrestins 在调控 β 细胞功能方面起着关键作用,包括在依赖 GPCR 和不依赖 GPCR 的途径中调控 β 细胞生长和胰岛素分泌。在这篇综述中,我们将介绍有关 GPCR 信号传导的最新见解以及 GRK 功能在调节 β 细胞生理机能方面的重要性。意义声明:胰腺 β 细胞含有多种多样的 G 蛋白偶联受体(GPCR),这些受体已被证明可改善 β 细胞的功能和存活率,但只有少数几种 GPCR 已成功地成为治疗糖尿病的靶点。这篇综述讨论了我们对β细胞GPCR药理学和GPCR激酶调控的最新理解进展,同时还强调了研究大部分尚未开发的富含β细胞的GPCR以揭示新型治疗策略的必要性。
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The Role of G Protein-Coupled Receptors and Receptor Kinases in Pancreatic β-Cell Function and Diabetes.

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can help to maintain normal blood glucose levels in individuals with chronic disease, many of these medicines are outdated, have severe side effects, and often become less efficacious over time, necessitating the need for insulin therapy.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. SIGNIFICANCE STATEMENT: 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.

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来源期刊
Pharmacological Reviews
Pharmacological Reviews 医学-药学
CiteScore
34.70
自引率
0.50%
发文量
40
期刊介绍: Pharmacological Reviews is a highly popular and well-received journal that has a long and rich history of success. It was first published in 1949 and is currently published bimonthly online by the American Society for Pharmacology and Experimental Therapeutics. The journal is indexed or abstracted by various databases, including Biological Abstracts, BIOSIS Previews Database, Biosciences Information Service, Current Contents/Life Sciences, EMBASE/Excerpta Medica, Index Medicus, Index to Scientific Reviews, Medical Documentation Service, Reference Update, Research Alerts, Science Citation Index, and SciSearch. Pharmacological Reviews offers comprehensive reviews of new pharmacological fields and is able to stay up-to-date with published content. Overall, it is highly regarded by scholars.
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