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

Abstract

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.

Conditional Knock-out Reveals a Requirement for O-Linked N-Acetylglucosaminase (O-GlcNAcase) in Metabolic Homeostasis

“…These findings are consistent with our previous report suggesting that OGT overexpression in muscle and fat under the GLUT4 promoter induced hyperleptinemia and insulin resistance in a sexually dimorphic fashion (54). Elevation of UDP-GlcNAc by glutamine fructose-6-phosphate amidotransferase overexpression induced a similar phenotype in mice (67-70) These findings and other studies suggest that adipokine changes associated with elevated O-GlcNAcylation in adipose tissues could be enough to trigger insulin resistance in other organs (71,72).…”

Fat intake leads to differential response of rat adipocytes to glucose, insulin and ascorbic acid

“…In fact, we observed a protective effect for this molecule against HG toxicity. This finding could be due to competition with glucose for GLUT-1, and -4 transporters 35,36 , reducing the effects of glucose on the hexosamine flux pathway 57 . Consequently, this situation could avoid cell death in control cells and possibly improve insulin sensitivity, since glucose toxicity contributes to insulin-resistance 58 .…”

Deep congenic analysis identifies many strong, context-dependent QTLs, one of which, Slc35b4, regulates obesity and glucose homeostasis

“…Slc35b4 encodes a protein that transports UDP-xylose and UDP-N-acetylglucosamine from the cytosol into the golgi and may therefore alter the bioavailability of its cargo nucleotide sugars for post-translational modification (Ashikov et al 2005). More than 600 proteins, including the insulin receptor IRS1, NOTCH, AKT, and AMPK, are modified with the addition of an UDP-xylose or UDP-N-acetylglucosamine moiety and may therefore contribute to the pleiotropic presentation of T2D and insulin resistance (Love and Hanover 2005;Yang et al 2008;Teo et al 2010). Interestingly, a SNP in the human SLC35B4 gene (rs1619682) is associated with waist circumference (Fox et al 2007), and chromosome 7q33, where SLC35B4 is located, is associated with variation in body mass index (BMI), metabolic syndrome, fasting glucose, pro-insulin levels, and fat stores (Arya et al 2002;Feitosa et al 2002;Tang et al 2003;Saunders et al 2007;Laramie et al 2008).…”