Pleiotropic and age-dependent effects of decreased protein modification by O-linked N-acetylglucosamine on pancreatic β-cell function and vascularization

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.     

Dynamic interplay between O-GlcNAc and O-phosphate: the sweet side of protein regulation

Beta-O-linked N-acetylglucosamine (O-GlcNAc) is an abundant modification of cytosolic and nuclear proteins that occurs in metazoans. O-GlcNAc is dynamically processed by a unique set of enzymes that actively add and remove the modification. Functionally, O-GlcNAc appears to regulate protein stability, subcellular localization and protein-protein interactions. The modification often acts in a reciprocal manner to O-phosphate modifications of proteins and together they can synergistically control the activity of many cellular processes. Recently, O-GlcNAc has been demonstrated to play a significant role in diseases such as diabetes, cancer and neurodegeneration. For example, the increased levels of O-GlcNAc that occur in diabetes are associated with decreased insulin responsiveness in adipocytes.