title: Pleiotropic and age-dependent effects of decreased protein modification by O-linked N-acetylglucosamine on pancreatic β-cell function and vascularization.
abstract: The hexosamine biosynthesis pathway (HBP) regulates the post-translational modification of nuclear and cytoplasmic protein by O-linked N-acetylglucosamine (O-GlcNAc). Numerous studies have demonstrated increased flux through this pathway contributes to the development of β-cell dysfunction. The effect of decreased O-GlcNAc on the maintenance of normal β-cell function, however, is not well understood. We studied transgenic mice that over express β-N-acetylglucosaminidase (O-GlcNAcase), an enzyme that catalyzes the removal of O-GlcNAc from proteins, in the pancreatic β-cell under control of the rat insulin promoter. 3-4-Month-old O-GlcNAcase transgenic mice have higher glucose excursions with a concomitant decrease in circulating insulin levels, insulin mRNA levels, and total islet insulin content. In older (8-9-month-old) O-GlcNAcase transgenic mice glucose tolerance is no longer impaired. This is associated with increased serum insulin, islet insulin content, and insulin mRNA in the O-GlcNAcase transgenic mice. These improvements in β-cell function with aging are associated with increased angiogenesis and increased VEGF expression, with parallel increases in activation of Akt and expression of PGC1α. The biphasic effects as a function of age are consistent with published observations of mice with increased O-GlcNAc in islets and demonstrate that O-GlcNAc signaling exerts multiple effects on both insulin secretion and islet survival.
authors.affiliation: Departments of Biochemistry, University of Utah School ofMedicine, Salt Lake City, Utah 84132, USA.
authors.forename: Yudi
authors.initials: Y
authors.lastname: Soesanto
authors.forename: Bai
authors.initials: B
authors.lastname: Luo
authors.forename: Glendon
authors.initials: G
authors.lastname: Parker
authors.forename: Deborah
authors.initials: D
authors.lastname: Jones
authors.forename: Robert C
authors.initials: RC
authors.lastname: Cooksey
authors.forename: Donald A
authors.initials: DA
authors.lastname: McClain
mesh_terms: D000117:Acetylglucosamine / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D005260:Female; D058685:Genetic Pleiotropy; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010100:Oxygen; D011401:Promoter Regions, Genetic / Q000235:genetics; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D012333:RNA, Messenger; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D010100:Oxygen; D000117:Acetylglucosamine