The Role of G Protein–Coupled Receptors and Receptor Kinases in Pancreaticβ-Cell Function and Diabetes

Abstract

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can help to maintain normal blood glucose levels in individuals with chronic disease, many of these medicines are outdated, have severe side effects, and often become less efficacious over time, necessitating the need for insulin therapy.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

Ca2+ signaling and metabolic stress-induced pancreatic β-cell failure

“…Moreover, while the rise of [Ca 2+ ] i is principally metabolism-driven, insulin exocytosis is modulated by many other agents including many hormones, fatty and amino acids, and neurotransmitters in so-called “amplifying pathways”. Many of these agents act by binding to G protein-coupled receptors (GPCRs), and the activation of phospholipase C (PLC)/protein kinase C (PKC) or adenylate cyclase (AC)/protein kinase A (PKA) pathways which rely on Ca 2+ for signaling ( 27 – 30 ). An extended model ( Figure 1B ) recognizes both the role of other agents in modulating insulin secretion, and the critically important role of Ca 2+ in other organelles.…”

Exploring the mediating role of calcium homeostasis in the association between diabetes mellitus, glycemic traits, and vascular and valvular calcifications: a comprehensive Mendelian randomization analysis

“…Diabetes mellitus (DM) has become an increasingly prevalent and potentially devastating medical condition, now recognized as a significant global health concern [ 1 ]. The morbidity and mortality associated with DM are primarily due to its complications.…”