290:1-8, 2006. doi:10.1152/ajpendo.00329.2005 AJP - EndoMaria G. Buse of diabetes: current status Hexosamines, insulin resistance, and the complications You might find this additional information useful...89 articles, 70 of which you can access free at: This article cites http://ajpendo.physiology.org/cgi/content/full/290/1/E1#BIBLon the following topics: http://highwire.stanford.edu/lists/artbytopic.dtlcan be found at Medline items on this article's topics Medicine .. Diabetes Oncology .. Insulin Resistance Biophysics .. Sarcoplasmic Reticulum Biochemistry .. Plasminogen Immunology .. Transcription Factors Pharmacology .. Plasminogen Activators including high-resolution figures, can be found at: Updated information and services http://ajpendo.physiology.org/cgi/content/full/290/1/E1 can be found at: AJP - Endocrinology and Metabolismabout Additional material and information http://www.the-aps.org/publications/ajpendoThis information is current as of April 18, 2006 . http://www.the-aps.org/.20814-3991. Copyright © 2005 by the American Physiological Society. ISSN: 0193-1849, ESSN: 1522-1555. Visit our website at organization. It is published 12 times a year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD publishes results of original studies about endocrine and metabolic systems on any level ofAJP - Endocrinology and Metabolism on April 18, 2006 ajpendo.physiology.orgDownloaded fromInvited ReviewHexosamines, insulin resistance, and the complications of diabetes: current statusMaria G. BuseDepartment of Medicine, Division of Endocrinology, Diabetes and MedicalGenetics, Medical University of South Carolina, Charleston, South CarolinaBuse, Maria G. Hexosamines, insulin resistance, and the complications ofdiabetes: 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 toglucosamine 6-phosphate, catalyzed by the first and rate-limiting enzyme glu-tamine:fructose-6-phosphate amidotransferase (GFAT). The major end product isUDP-N-acetylglucosamine (UDP-GlcNAc). Along with other amino sugars gener-ated by HBP, it provides essential building blocks for glycosyl side chains, ofproteins and lipids. UDP-GlcNAc regulates flux through HBP by regulating GFATactivity and is the obligatory substrate of O-GlcNAc transferase. The latter is acytosolic and nuclear enzyme that catalyzes a reversible, posttranslational proteinmodification, transferring GlcNAc in O-linkage (O-GlcNAc) to specific serine/threonine residues of proteins. The metabolic effects of increased flux through HBPare thought to be mediated by increasing O-GlcNAcylation. Several investigatorsproposed that HBP functions as a cellular nutrient sensor and plays a role in thedevelopment of insulin resistance and the vascular complications of diabetes.Increased flux through HBP is required and sufficient for some of the metaboliceffects of sustained, increased glucose flux, which promotes the complications ofdiabetes, e.g., diminished expression of sarcoplasmic reticulum Ca2⫹-ATPase incardiomyocytes and induction of TGF-␤ and plasminogen activator inhibitor-1 invascular smooth muscle cells, mesangial cells, and aortic endothelial cells. Themechanism was consistent with enhanced O-GlcNAcylation of certain transcriptionfactors. The role of HBP in the development of insulin resistance has beencontroversial. There are numerous papers showing a correlation between increasedflux through HBP and insulin resistance; however, the causal relationship has notbeen established. More recent experiments in mice overexpressing GFAT in muscleand adipose tissue or exclusively in fat cells suggest that the latter develop in vivoinsulin resistance via cross talk between fat cells and muscle. Although therelationship between HBP and insulin resistance may be quite complex, it clearlydeserves further study in concert with its role in the complications of diabetes.hexosamine biosynthesis pathway; N-acetylglucosamine; O-linked N-acetylglu-cosamine; modification of proteinsINSULIN RESISTANCE IS A HALLMARK of type 2 diabetes, of uncon-trolled type 1 diabetes, and of obesity and the metabolicsyndrome (91) and is associated with numerous other condi-tions, such as cystic fibrosis, uremia, septicemia, glucocorti-coid excess, polycystic ovary syndrome, etc. Clinically, insulinresistance is defined as the reduced ability of insulin to lowerplasma glucose, which reflects in great part impaired insulin-stimulated glucose transport into tissues, which express theinsulin-responsive glucose transporter GLUT4 (skeletal andheart muscle and adipocytes). Except for a few rare conditions,the major defect(s) is downstream of insulin’s binding to itsreceptors. Type 2 diabetes is a polygenic disease, and severalrecent, excellent reviews discuss the insulin receptor signalingcascade and proposed mechanisms of impaired signal trans-duction in insulin resistance (57, 69, 70, 72). The propensity toinsulin resistance is likely genetically determined (79); how-ever, the expression of the phenotype is modulated by variousfactors, including diet, exercise, and aging.Sustained hyperglycemia causes insulin resistance in hu-mans (89) and in animal models (67), which leads to theconcept of “glucose toxicity.” The latter accounts for theinsulin resistance in uncontrolled type 1 diabetes (89). Simi-larly, sustained elevations of circulatory nonesterified fattyacids (NEFA) also induce insulin resistance (“lipotoxicity”).Thus insulin resistance may represent an adaptive mechanismthat may serve to protect cells from the deleterious effects ofexcessive nutrient flux, such as oxidative stress. This wouldimply the existence of cellular biochemical sensors, whichmonitor the flux of nutrients. McGarry (47) first identifiedmalonyl-CoA as a biochemical sensor that regulates the switchfrom fatty acid to glucose oxidation in the liver. Severallaboratories have proposed that flux through the hexosaminesynthesis pathway (HSP) may function as a cellular nutrientsensor and play a role in the development of insulin resistanceand the vascular complications of diabetes (4, 5, 24, 44, 66).This review addresses the experimental evidence that supportsand questions this hypothesis and the proposed mechanisms bywhich the HSP may exert these effects.A role for excess glucose flux via HSP in insulin