{"title":"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","authors":"Matthew J Varney, Jeffrey L Benovic","doi":"10.1124/pharmrev.123.001015","DOIUrl":null,"url":null,"abstract":"<p><p>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can help to maintain normal blood glucose levels in individuals with chronic disease, many of these medicines are outdated, have severe side effects, and often become less efficacious over time, necessitating the need for insulin therapy.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 <i>β</i> cells, GPCRs regulate <i>β</i>-cell growth, apoptosis, and insulin secretion, which are all critical in maintaining sufficient <i>β</i>-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 <i>β</i> cell serve a critical role in the regulation of <i>β</i>-cell function, including <i>β</i>-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 <i>β</i>-cell physiology. SIGNIFICANCE STATEMENT: Pancreatic <i>β</i> cells contain a diverse array of G protein-coupled receptors (GPCRs) that have been shown to improve <i>β</i>-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 <i>β</i>-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.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":"76 2","pages":"267-299"},"PeriodicalIF":19.3000,"publicationDate":"2024-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10877731/pdf/","citationCount":"0","resultStr":"{\"title\":\"The Role of G Protein-Coupled Receptors and Receptor Kinases in Pancreatic <i>β</i>-Cell Function and Diabetes.\",\"authors\":\"Matthew J Varney, Jeffrey L Benovic\",\"doi\":\"10.1124/pharmrev.123.001015\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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 <i>β</i> cells, GPCRs regulate <i>β</i>-cell growth, apoptosis, and insulin secretion, which are all critical in maintaining sufficient <i>β</i>-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 <i>β</i> cell serve a critical role in the regulation of <i>β</i>-cell function, including <i>β</i>-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 <i>β</i>-cell physiology. SIGNIFICANCE STATEMENT: Pancreatic <i>β</i> cells contain a diverse array of G protein-coupled receptors (GPCRs) that have been shown to improve <i>β</i>-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 <i>β</i>-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.</p>\",\"PeriodicalId\":19780,\"journal\":{\"name\":\"Pharmacological Reviews\",\"volume\":\"76 2\",\"pages\":\"267-299\"},\"PeriodicalIF\":19.3000,\"publicationDate\":\"2024-02-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10877731/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pharmacological Reviews\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1124/pharmrev.123.001015\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pharmacological Reviews","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1124/pharmrev.123.001015","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
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.
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.