BIOCHEMICAL MECHANISMS OF IN VIVO INSULIN RESISTANCE

虽然“胰岛素抵抗”可能有多种主要原因， 胰岛素促进骨骼肌葡萄糖能力受损 转运和/或磷酸化是一个反复出现的特征。 对这一观察结果的一个可能解释是， 中度葡萄糖耐受不良（即β细胞和/或肝缺陷） 或细胞内葡萄糖的主要途径中的原发性损害 处理（即糖原合成和/或糖酵解）可能会导致 胰岛素抵抗综合征的表现通过一个共同的生化 通路 马歇尔及其同事利用脂肪细胞的原代培养物， 细胞中葡萄糖转运系统的脱敏 与高浓度葡萄糖和胰岛素孵育需要代谢 氨基己糖生物合成途径中的葡萄糖。 如果这样的监管 途径在体内骨骼肌中起作用， 降低葡萄糖转运系统对胰岛素的敏感性， 一个有吸引力的统一假设， 对大多数胰岛素抵抗的葡萄糖转运/磷酸化的作用 states. 事实上，增加葡萄糖碳通过 葡萄糖胺途径可能是由于持续升高， 细胞内果糖-6-磷酸浓度由于任一或两者 葡萄糖利用率增加，即慢性 高血糖症/高胰岛素血症，以及通过糖酵解的处置减少 和/或糖原合成。 因此，高血糖症 导致胰岛素对葡萄糖转运/磷酸化的作用受损， 揭示了一个更基本的“反馈控制系统”， 调节细胞葡萄糖摄取，以响应持续增加的 磷酸己糖的细胞内利用率。 我们的建议将试图确定顺序出现的 糖尿病患者肝脏和骨骼肌葡萄糖代谢缺陷 慢性高血糖和中度低胰岛素血症的糖尿病模型， 他们的逆转后，纠正慢性的时间过程， 根皮苷治疗高血糖。 特别是示踪方法 最近在有意识的大鼠中开发的，应该让我们澄清 缺陷性葡萄糖诱导的肝抑制的作用 胰岛素介导的抑制作用受损 骨骼肌糖原分解对葡萄糖诱导的 胰岛素抵抗 我们还将研究是否代谢的 葡萄糖通过葡萄糖胺途径具有重要的调节作用 在体内葡萄糖诱导的脱敏中， 脂肪细胞的培养以及是否可以诱导这种脱敏 通过损害细胞内葡萄糖的处置，即使在 没有持续的高血糖。

Though "insulin resistance" is likely to have multiple primary causes, the impairment in insulin's ability to promote skeletal muscle glucose transport and/or phosphorylation is a recurrent feature. A possible explanation for this observation is that a primary cause of either moderate glucose intolerance (ie, beta cell and/or hepatic defect) or a primary impairment in a major pathway of intracellular glucose disposal (ie, glycogen synthesis and/or glycolysis) may cause the full expression of the insulin resistance syndrome through a common biochemical pathway. Using primary cultures of adipose cells, Marshall and colleagues suggested that the desensitization of the glucose transport system in cells incubated with high levels of glucose and insulin required the metabolism of glucose in the hexosamine biosynthesis pathway. If such a regulatory pathway is operating in skeletal muscle in vivo and is capable of desensitizing the glucose transport system to insulin, it would represent an attractive unifying hypothesis for the presence of defective insulin action on glucose transport/phosphorylation in most insulin resistant states. In fact, increased routing of glucose carbons through the glucosamine pathway could result from a sustained elevation in intracellular fructose-6-phosphate concentrations due to either or both increased glucose availability, ie, chronic hyperglycemia/hyperinsulinemia, and decreased disposal through glycolysis and/or glycogen synthesis. Thus, the mechanism by which hyperglycemia begets impaired insulin action on glucose transport/phosphorylation may shed light on a more fundamental "feed-back control system" which down- regulates cellular glucose uptake in response to a sustained increase in the intracellular availability of hexose-phosphates. Our proposal will attempt to identify the sequential appearance of metabolic defects in hepatic and skeletal muscle glucose metabolism in a diabetic model of chronic hyperglycemia and moderate hypoinsulinemia and the time-course of their reversal following correction of chronic hyperglycemia by phlorizin treatment. In particular, tracer methodologies recently developed in the conscious rat should allow us to clarify the role of defective glucose-induced suppression of hepatic gluconeogenesis/glycogenolysis and of impaired insulin-mediated inhibition of skeletal muscle glycogenolysis to the development of glucose-induced insulin resistance. We will also examine whether the metabolism of glucose through the glucosamine pathway has the important regulatory role in in vivo glucose-induced desensitization which was suggested in primary culture of adipose cells and whether such a desensitization can be induced through the impairment of intracellular glucose disposal even in the absence of sustained hyperglycemia.