G Protein-Coupled Receptors and Insulin Secretion: 119 and Counting

Abstract

Type 2 diabetes mellitus is an increasingly prevalent disease throughout the world, with dramatic consequences in terms of individual well-being, public health, and economy. It is due to a combination of defective insulin secretion from the pancreatic β-cell and impaired sensitivity of the peripheral tissues to insulin. Because of the key role of β-cell dysfunction in the pathogenesis of type 2 diabetes, the pharmaceutical industry has devoted major efforts in recent years towards developing drugs that can enhance insulin secretion and preserve β-cell function. Such efforts have been somewhat hampered by our incomplete understanding of the mechanisms of insulin secretion. Glucose-stimulated insulin secretion (GSIS) is controlled by a “triggering” pathway, which involves glucose metabolism, membrane depolarization, and insulin exocytosis, as well as an “amplifying” pathway, which potentiates the former (1) (Figure 1). Whereas the nature of the amplifying signals is still debated, ample evidence implies a role for lipid-derived signaling molecules in this process (2). A number of nutrients, hormones, and neurotransmitters can influence GSIS, and most of these act through G-protein coupled receptors (GPCRs). Whereas the majority of GPCRs initially identified in the β-cell inhibit insulin secretion (3), the last few years have seen a multitude of papers ascribing stimulatory functions to newly discovered GPCRs (Figure 1). The number of β-cell GPCRs involved in the control of insulin secretion has increased steadily and to date, there are 6–7 different known G-protein-coupled mechanisms. Except for glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which are polypeptides and whose receptors are Class-B GPCRs (4), almost all of the other insulin secretagogue GPCR ligands are lipidic in nature and their cognate receptors belong to the Class-A GPCRs. These include free-fatty acids (FFA) (GPR40) (5–7), 2-arachidonylglycerol / anandamide (CB1/2R) (8), and acetylcholine (M3-muscarinic receptor) (9). In this issue, Chu et al. (10) further demonstrate that the oleoylethanolamide (OEA) / lysophosphatidylcholine (LPC)-activated GPR119 is involved in GSIS (10). Figure 1 GPCR-mediated amplification of insulin secretion