Hexosamines as mediators of nutrient sensing and regulation in diabetes
Hexosamines as mediators of nutrient sensing and regulation in diabetes
复制标题
DOI：
10.1016/s1056-8727(01)00188-x
复制
发表时间：
2002-01-01
影响因子：
3
通讯作者：
McClain, DA
中科院分区：
文献类型：
--
作者：
McClain, DA
高浓度的葡萄糖诱导胰岛素抵抗，损害胰岛素分泌，并以反映2型糖尿病的方式影响肝脏葡萄糖产生，而己糖胺模拟许多这些作用。这导致了细胞使用己糖胺通量作为葡萄糖和饱腹感传感途径的假设。已通过在包括肌肉、肝脏、脂肪和β细胞在内的几种组织中过表达己糖胺合成的限速酶谷氨酰胺：果糖-6-磷酸酰胺转移酶（GFA）来验证葡萄糖感知的己糖胺假说。随着转基因动物中GFA的过表达，骨骼肌变得胰岛素抵抗，肝脏合成过量的脂肪酸，并且β细胞分泌过量的胰岛素负荷以导致高胰岛素血症。因此，过量的己糖胺流量导致协调反应，从而燃料被分流到长期储存，反映了“节俭表型”。“然而，长期而言，这些相同的适应性变化最终导致肥胖、高脂血症、β细胞衰竭和2型糖尿病。这些结果提示了慢性营养过剩导致2型糖尿病表型的机制。(C)2002年爱思唯尔科学公司All rights reserved.
High concentrations of glucose induce insulin resistance, impair insulin secretion, and affect hepatic glucose production in a manner that mirrors Type 2 diabetes, and hexosamines mimic many of these effects. This has led to the hypothesis that cells use hexosamine flux as a glucose- and satiety-sensing pathway. The hexosamine hypothesis for glucose sensing has been validated by overexpressing the rate-limiting enzyme for hexosamine synthesis, glutamine: fructose-6-phosphate amidotransferase (GFA) in several tissues including muscle, liver, fat, and beta cells. With overexpression of GFA in transgenic animals, skeletal muscle becomes insulin resistant, the liver synthesizes excess fatty acid, and the beta cell secretes excess insulin loading to hyperinsulinemia. Thus, excess hexosamine flux leads to a coordinated response whereby fuel is shunted toward long-term storage, mirroring the "thrifty phenotype." Chronically, however, these same adaptive changes result ultimately in obesity, hyperlipidemia, beta cell failure, and Type 2 diabetes. These results suggest a mechanism by which chronic overnutrition leads to the phenotype of Type 2 diabetes. (C) 2002 Elsevier Science Inc. All rights reserved.