Buse Maria G
Department of Medicine, Division of Endocrinology, Diabetes and Medical Genetics, Medical University of South Carolina, Charleston, SC 29425, USA.
Am J Physiol Endocrinol Metab. 2006 Jan;290(1):E1-E8. 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 Ca(2+)-ATPase in cardiomyocytes and induction of TGF-beta 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 GFAT in muscle and adipose tissue or exclusively in fat cells suggest that the latter develop in vivo insulin resistance via cross talk between fat cells and muscle. Although the relationship between HBP and insulin resistance may be quite complex, it clearly deserves further study in concert with its role in the complications of diabetes.
己糖胺生物合成途径（HBP）是糖酵解的一个相对较小的分支。6-磷酸果糖在首个限速酶谷氨酰胺：6-磷酸果糖氨基转移酶（GFAT）的催化下转化为6-磷酸葡糖胺。主要终产物是UDP-N-乙酰葡糖胺（UDP-GlcNAc）。它与HBP产生的其他氨基糖一起，为蛋白质和脂质的糖基侧链提供必需的结构单元。UDP-GlcNAc通过调节GFAT活性来调节HBP的通量，并且是O-连接N-乙酰葡糖胺转移酶的必需底物。后者是一种胞质和核酶，催化一种可逆的翻译后蛋白质修饰，将O-连接（O-GlcNAc）的GlcNAc转移到蛋白质的特定丝氨酸/苏氨酸残基上。HBP通量增加的代谢效应被认为是通过增加O-糖基化来介导的。几位研究者提出，HBP作为一种细胞营养传感器，在胰岛素抵抗的发展以及糖尿病的血管并发症中发挥作用。持续增加的葡萄糖通量会促进糖尿病并发症，例如心肌细胞中肌浆网Ca(2+)-ATP酶表达减少以及血管平滑肌细胞、系膜细胞和主动脉内皮细胞中TGF-β和纤溶酶原激活物抑制剂-1的诱导，而HBP通量增加对于其中一些代谢效应是必需且充分的。其机制与某些转录因子的O-糖基化增强一致。HBP在胰岛素抵抗发展中的作用一直存在争议。有许多论文表明HBP通量增加与胰岛素抵抗之间存在关联；然而，因果关系尚未确立。最近在肌肉和脂肪组织中或仅在脂肪细胞中过表达GFAT的小鼠实验表明，后者通过脂肪细胞与肌肉之间的相互作用在体内产生胰岛素抵抗。尽管HBP与胰岛素抵抗之间的关系可能相当复杂，但显然值得结合其在糖尿病并发症中的作用进行进一步研究。
