The Journal of Physical Fitness and Sports Medicine
Online ISSN : 2186-8123
Print ISSN : 2186-8131
ISSN-L : 2186-8131
Short Review Article
Physiological relevance of protein-glycosylation to pathogenesis of diabetes
Kazuaki OhtsuboNaoyuki Taniguchi
ジャーナル フリー

2014 年 3 巻 2 号 p. 223-228


Pancreatic β cells express glucose transporter-2 (GLUT2) on the cell surface as a glucose sensor molecule for appropriate insulin secretion. 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. Glycobiology and mouse genetics revealed that GnT-IV is a glycosyltransferase indispensable for increasing the N-glycan branch complexity of GLUT2, which provides 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 pathophysiological 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 and, subsequently, attenuated GnT-IVa-dependent GLUT2 glycosylation. Engineering and characterizing of transgenic mice overexpressing GnT-IVa in pancreatic β cells revealed that maintenance of GnT-IVa-dependent protein glycosylation prevents high fat diet-induced β cell dysfunction and ameliorates the onset of type 2 diabetes. These findings indicate that GnT-IV-mediated organization of cell surface GLUT2 is a fundamental process to modulate insulin secretion responses to fluctuating extracellular glucose levels, a paradigm that can be practically applied to better understand the pathogenesis of type 2 diabetes and development of drugs.

© 2014 The Japanese Society of Physical Fitness and Sports Medicine
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