Newer perspective on the coupling between glucose-mediated signaling and β-cell functionality

Abstract

Insulin secretion by the pancreatic β-cells is elicited in response to elevated extracellular glucose concentration. In addition to triggering insulin secretion, glucose-induced signal regulates β-cell proliferation and survival. However, the molecular mechanism underlying the effects of glucose on the β-cell functionality still remains unclear. Glucokinase, a hexokinase isozyme that catalyzes the phosphorylation of glucose, acts as the glucose sensor in the β-cells. To investigate the mechanisms of glucose signaling in the regulation of β-cell functions, we analyzed the role of glucokinase in insulin secretion, β-cell proliferation and β-cell apoptosis, using β-cell-specific glucokinase-haploinsufficient (Gck+/–) mice and allosteric glucokinase activators (GKAs). Glucokinase-mediated glucose metabolism (1) suppresses endoplasmic reticulum (ER) stress-induced β-cell apoptosis via inducing insulin receptor substrate-2 (IRS-2) expression and expression of ER stress-related molecules, (2) promotes adaptive β-cell proliferation through activation of the Forkhead Box M1 (FoxM1)/polo-like kinase-1 (PLK1)/centromere protein-A (CENP-A) pathway, (3) induces islet inflammation by promoting interaction of islet-derived S100 calcium-binding protein A8 (S100A8) with macrophages, (4) induces the expression of Fibulin-5 (Fbln5), an extracellular matrix protein to regulate β-cell functions, and (5) activates other unknown pathways. Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors have been found to possibly compensate for dysregulation of glucose metabolism in the β-cells. This review provides an update and overview of the recent advances in the study of β-cell pathophysiology and some therapeutic possibilities focusing on glucose-/glucokinase-mediated signaling.