Glyco-Predisposing Factor of Diabetes

Abstract

Appropriate insulin secretion is an essential process in glucose homeostasis and is initiated by glucose sensing with glucose transporter-2 (GLUT2) in pancreatic β-cells. The disappearance of GLUT2 from the β-cell surface is one of the early markers of the onset of type 2 diabetes, though the molecular mechanism has not been well understood. Recent advance in glycophysiology revealed that specific GLUT2 glycosylation by GnT-IVa is required for the production of carbohydrate epitopes bound to galectin-9 on the β-cell surface. The engagement of galectin-9 with GLUT2 regulates remodeling of GLUT2 clusters among cell surface membrane sub-domains, to control glucose transport activities, and prevents endocytosis to increase cell surface residency of GLUT2 that contributes to sustaining the glucose sensor function of β-cells. The pathway to diet- and obesity-associated diabetes has recently been revealed, in which a high-fat diet leading to diabetes recapitulated the free fatty acid-induced oxidative stress in human and mouse pancreatic β-cells that induced nuclear exclusion of transcription factors regulating GnT-IVa and, subsequently, attenuated GnT-IVa-dependent GLUT2 glycosylation. In β-cells, overexpression of GnT-IVa prevents GLUT2 glycosylation and high-fat diet-induced β-cell dysfunction that ameliorates the onset of type 2 diabetes. These findings indicate that GnT-IV-mediated redistribution of cell surface GLUT2 is a fundamental process to regulate insulin secretion responses to blood glucose levels, a paradigm that can be practically applied to better understand the pathogenesis of type 2 diabetes and provide a clue for the development of drugs.