Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes.
Pancreatic beta cell-surface expression of glucose transporter 2 (Glut-2) is essential for glucose-stimulated insulin secretion, thereby controlling blood glucose homeostasis in response to dietary intake. We show that the murine GlcNAcT-IVa glycosyltransferase is required for Glut-2 residency on the beta cell surface by constructing a cell-type- and glycoprotein-specific N-glycan ligand for pancreatic lectin receptors. Loss of GlcNAcT-IVa, or the addition of glycan-ligand mimetics, attenuates Glut-2 cell-surface half-life, provoking endocytosis with redistribution into endosomes and lysosomes. The ensuing impairment of glucose-stimulated insulin secretion leads to metabolic dysfunction diagnostic of type 2 diabetes. Remarkably, the induction of diabetes by chronic ingestion of a high-fat diet is associated with reduced GlcNAcT-IV expression and attenuated Glut-2 glycosylation coincident with Glut-2 endocytosis. We infer that beta cell glucose-transporter glycosylation mediates a link between diet and insulin production that typically suppresses the pathogenesis of type 2 diabetes.
Ohtsubo
Kazuaki
K
Howard Hughes Medical Institute and Department of Cellular and Molecular Medicine, 9500 Gilman Drive, University of California, San Diego, La Jolla, CA 92093, USA.
Takamatsu
Shinji
S
Minowa
Mari T
MT
Yoshida
Aruto
A
Takeuchi
Makoto
M
Marth
Jamey D
JD
D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control*; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism*; D006031:Glycosylation; D007328:Insulin / Q000096:biosynthesis* / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017351:N-Acetylglucosaminyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D004041:Dietary Fats; D051273:Glucose Transporter Type 2; D007328:Insulin; C495682:Slc2a2 protein, mouse; C508256:Mgat14 protein, mouse; D017351:N-Acetylglucosaminyltransferases; C090677:UDP-GlcNAc-GlcNAc-R 1-4-N-acetylglucosaminyltransferase