Glucagon‐like peptide 1‐potentiated insulin secretion and proliferation of pancreatic β‐cells GLP‐1促进胰岛素分泌和胰岛β细胞增殖的机制

Abstract

Glucagon-like peptide-1 (GLP-1) is the primary incretin hormone secreted from the intestine upon uptake of food to stimulate insulin secretion from pancreatic β-cells. GLP-1 exerts its effects by binding to its G-protein coupled receptors and subsequently activating adenylate cyclase, leading to generation of cyclic adenosine monophosphate (cAMP). cAMP stimulates insulin secretion via activation of its effectors PKA and Epac2 in pancreatic β-cells. In addition to its insulinotropic effects, GLP-1 also preserves pancreatic β-cell mass by stimulating β-cell proliferation. Unlike the action of sulphonylureas in lowering blood glucose levels, action of GLP-1 is affected by and interplays with glucose levels. Due to such advantages, GLP-1-based therapeutics have been rapidly developed and used clinically for treatment of type 2 diabetes. However, molecular mechanisms underlying how GLP-1 potentiates diminished glucose-stimulated insulin secretion and β-cell proliferation under diabetic conditions are not well understood. Here, we review the actions of GLP-1 in regulation of insulin secretion and pancreatic β-cell proliferation.

Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development

“…In addition to Ca 2ϩ , cAMP signaling also play important role in regulating insulin secretion. The involvement of EPAC proteins, particularly EPAC2, in transducing cAMP-mediated potentiation of insulin exocytosis has been well documented by in vitro and in vivo analyses, and reviewed extensively (14,427,429,594,595,648,933,1022). Therefore, the following section will focus mainly on the more recently published studies of the function of EPAC in pancreas.…”

DNA methylation in the pathogenesis of type 2 diabetes in humans

“…The initial studies on human islets were candidate driven and investigated genes with known importance in β-cell function or cellular metabolism ( Table 1 and Figure 1 ). These studies identified that the promoters of INS [4] (encoding insulin), PDX1 [5] (encoding a transcription factor important for both pancreatic development [6] and the function of mature β-cells [7] ), PPARGC1A [8] (encoding the mitochondrial regulator PGC1α [9] ), and GLP1R [10] (encoding the GLP1 receptor which stimulates insulin secretion and enhances/protects β-cell mass when activated [11] ) were all hypermethylated in islets from donors with T2D compared to islets from non-diabetic donors. Additionally, a higher methylation level was associated with reduced mRNA expression of the respective gene in the diabetic islets and with higher glycated hemoglobin A1c (HbA1c, a measure of long-term plasma glucose levels), suggesting a possible role in β-cell perturbation in T2D.…”

β Cell-specific deletion of guanylyl cyclase A, the receptor for atrial natriuretic peptide, accelerates obesity-induced glucose intolerance in mice

“…The molecular pathways that are activated and drive the increases in β-cell mass in obesity and insulin resistance have yet to be fully elucidated [ 38 ]. High glucose levels and incretine hormones such as GLP-1 might be involved [ 38 , 39 ]. Our data suggest that cardiac NPs, via GC-A/cGMP signaling, support these pathways and thereby the adaptative proliferation of β-cells during early stages of obesity-linked insulin resistance and metabolic syndrome.…”