Hexosamines insulin resistance and the complications of diabetes current status Maria G Buse AJP Endo 290 1 8 2006 doi 10 1152 ajpendo 00329 2005 You might find this additional information useful This article cites 89 articles 70 of which you can access free at http ajpendo physiology org cgi content full 290 1 E1 BIBL Medline items on this article s topics can be found at http highwire stanford edu lists artbytopic dtl on the following topics Pharmacology Plasminogen Activators Immunology Transcription Factors Biochemistry Plasminogen Biophysics Sarcoplasmic Reticulum Oncology Insulin Resistance Medicine Diabetes Additional material and information about AJP Endocrinology and Metabolism can be found at http www the aps org publications ajpendo This information is current as of April 18 2006 AJP Endocrinology and Metabolism publishes results of original studies about endocrine and metabolic systems on any level of organization It is published 12 times a year monthly by the American Physiological Society 9650 Rockville Pike Bethesda MD 20814 3991 Copyright 2005 by the American Physiological Society ISSN 0193 1849 ESSN 1522 1555 Visit our website at http www the aps org Downloaded from ajpendo physiology org on April 18 2006 Updated information and services including high resolution figures can be found at http ajpendo physiology org cgi content full 290 1 E1 Am J Physiol Endocrinol Metab 290 E1 E8 2006 doi 10 1152 ajpendo 00329 2005 Invited Review Hexosamines insulin resistance and the complications of diabetes current status Maria G Buse Department of Medicine Division of Endocrinology Diabetes and Medical Genetics Medical University of South Carolina Charleston South Carolina hexosamine biosynthesis pathway N acetylglucosamine O linked N acetylglucosamine modification of proteins INSULIN RESISTANCE IS A HALLMARK of type 2 diabetes of uncontrolled type 1 diabetes and of obesity and the metabolic syndrome 91 and is associated with numerous other conditions such as cystic fibrosis uremia septicemia glucocorticoid excess polycystic ovary syndrome etc Clinically insulin resistance is defined as the reduced ability of insulin to lower plasma glucose which reflects in great part impaired insulinstimulated glucose transport into tissues which express the insulin responsive glucose transporter GLUT4 skeletal and heart muscle and adipocytes Except for a few rare conditions the major defect s is downstream of insulin s binding to its receptors Type 2 diabetes is a polygenic disease and several recent excellent reviews discuss the insulin receptor signaling cascade and proposed mechanisms of impaired signal transduction in insulin resistance 57 69 70 72 The propensity to insulin resistance is likely genetically determined 79 however the expression of the phenotype is modulated by various factors including diet exercise and aging Address for reprint requests and other correspondence M G Buse Dept of Medicine Div of Endocrinology Diabetes and Medical Genetics Medical University of South Carolina Charleston SC 29425 e mail busemg musc edu http www ajpendo org Sustained hyperglycemia causes insulin resistance in humans 89 and in animal models 67 which leads to the concept of glucose toxicity The latter accounts for the insulin resistance in uncontrolled type 1 diabetes 89 Similarly sustained elevations of circulatory nonesterified fatty acids NEFA also induce insulin resistance lipotoxicity Thus insulin resistance may represent an adaptive mechanism that may serve to protect cells from the deleterious effects of excessive nutrient flux such as oxidative stress This would imply the existence of cellular biochemical sensors which monitor the flux of nutrients McGarry 47 first identified malonyl CoA as a biochemical sensor that regulates the switch from fatty acid to glucose oxidation in the liver Several laboratories have proposed that flux through the hexosamine synthesis pathway HSP may function as a cellular nutrient sensor and play a role in the development of insulin resistance and the vascular complications of diabetes 4 5 24 44 66 This review addresses the experimental evidence that supports and questions this hypothesis and the proposed mechanisms by which the HSP may exert these effects A role for excess glucose flux via HSP in insulin resistance was first proposed by Marshall et al in 1991 43 on the basis 0193 1849 06 8 00 Copyright 2006 the American Physiological Society E1 Downloaded from ajpendo physiology org on April 18 2006 Buse Maria G Hexosamines insulin resistance and the complications of diabetes current status Am J Physiol Endocrinol Metab 290 E1 E8 2006 doi 10 1152 ajpendo 00329 2005 The hexosamine biosynthesis pathway HBP is a relatively minor branch of glycolysis Fructose 6 phosphate is converted to glucosamine 6 phosphate catalyzed by the first and rate limiting enzyme glutamine fructose 6 phosphate amidotransferase GFAT The major end product is UDP N acetylglucosamine UDP GlcNAc Along with other amino sugars generated by HBP it provides essential building blocks for glycosyl side chains of proteins and lipids UDP GlcNAc regulates flux through HBP by regulating GFAT activity and is the obligatory substrate of O GlcNAc transferase The latter is a cytosolic and nuclear enzyme that catalyzes a reversible posttranslational protein modification transferring GlcNAc in O linkage O GlcNAc to specific serine threonine residues of proteins The metabolic effects of increased flux through HBP are thought to be mediated by increasing O GlcNAcylation Several investigators proposed that HBP functions as a cellular nutrient sensor and plays a role in the development of insulin resistance and the vascular complications of diabetes Increased flux through HBP is required and sufficient for some of the metabolic effects of sustained increased glucose flux which promotes the complications of diabetes e g diminished expression of sarcoplasmic reticulum Ca2 ATPase in cardiomyocytes and induction of TGF and plasminogen activator inhibitor 1 in vascular smooth muscle cells mesangial cells and aortic endothelial cells The mechanism was consistent with enhanced O GlcNAcylation of certain transcription factors The role of HBP in the development of insulin resistance has been controversial There are numerous papers showing a correlation between increased flux through HBP and insulin resistance however the causal relationship has not been established More recent experiments in mice overexpressing