Hexosamine flux, the O-GlcNAc modification, and the development of insulin resistance in adipocytes

Excess flux through the hexosamine biosynthesis pathway in adipocytes is a fundamental cause of “glucose toxicity” and the development of insulin resistance that leads to type II diabetes. Adipose tissue-specific elevation in hexosamine flux in animal models recapitulates whole-body insulin-resistant phenotypes, and increased hexosamine flux in adipocyte cell culture models impairs insulin-stimulated glucose uptake. Many studies have been devoted to unveiling the molecular mechanisms in adipocytes in response to excess hexosamine flux-mediated insulin resistance. As a major downstream event consuming and incorporating the final product of the hexosamine biosynthesis pathway, dynamic and inducible O-GlcNAc modification is emerging as a modulator of insulin sensitivity in adipocytes. Given that O-GlcNAc is implicated in both insulin-mediated signal transduction and transcriptional events essential for adipocytokine secretion, direct functional studies to pinpoint the roles of O-GlcNAc in the development of insulin resistance via excess flux through hexosamine biosynthesis pathway are needed.