MECHANISMS OF INSULIN RESISTANCE IN SKELETAL MUSCLE

描述：胰岛素抵抗是非胰岛素依赖者的重要危险因素。 胰岛素依赖型糖尿病(NIDDM) 高血压、动脉粥样硬化和心血管疾病。尽管它的 与许多健康问题有重大关联，其机制 潜在的胰岛素抵抗尚不清楚。《长河》 调查人员研究的长期目标是澄清 骨骼中胰岛素抵抗形成的细胞机制 肌肉，负责胰岛素介导的葡萄糖的主要组织 领悟。在此应用程序中，调查人员建议测试 假设在胰岛素抵抗的发展过程中受损 骨骼肌细胞内葡萄糖代谢的研究先于 导致胰岛素对葡萄糖转运的作用受损。这个 胰岛素降低对葡萄糖作用的假说的含义 运输(或摄取)是肌肉的一种次级适应性反应 防止底物在其葡萄糖吸收能力时积聚 新陈代谢减慢。为了检验这一假说，他们建议检验 骨骼肌葡萄糖代谢受损(例如， 糖酵解)先于胰岛素对葡萄糖转运作用的减少 在高脂肪胰岛素抵抗的慢性发展过程中 在老鼠身上进食。此外，他们还建议检查急性呼吸道感染 骨骼肌中葡萄糖代谢的抑制会导致随后 胰岛素对葡萄糖转运的下调作用 延长高胰岛素血症葡萄糖钳夹时间。调查人员还 建议研究氨基己糖的生物合成途径，最近 被发现调节培养的脂肪细胞中的胰岛素作用，作为一种 可能的机制将糖代谢受损与 胰岛素在骨骼肌中作用的调节。最后，如果这个角色 在骨骼肌中建立了氨基己糖途径，它们 建议研究以含有以下成分的饲料喂饲大鼠 氨基葡萄糖通过增加通透性导致胰岛素抵抗 通过己糖胺途径，如果是，胰岛素抵抗 导致随后的高血糖和/或胰岛素受损 分泌物。这项研究将为深入了解心力衰竭的机制提供帮助。 骨骼肌中胰岛素抵抗的发展，这是 NIDDM发病机制中的主要事件。

DESCRIPTION: Insulin resistance is a significant risk factor for non- insulin- dependent diabetes mellitus (NIDDM), hypertension,atherosclerosis, and cardiovascular disease. Despite its significant association with numerous health problems, the mechanisms underlying insulin resistance are not clearly understood. The long term objective of the investigators' research is to elucidate the cellular mechanisms by which insulin resistance is developed in skeletal muscle, the major tissue responsible for insulin-mediated glucose uptake. In this application the investigators propose to test the hypothesis that during the development of insulin resistance impairment of intracellular glucose metabolism in skeletal muscle precedes and causes impairment of insulin's action on glucose transport. The implication of the hypothesisis that reduced insulin action on glucose transport (or uptake) is a secondary and adaptive response of muscle to prevent accumulation of substrate when its capacity for glucose metabolism is reduced.To test this hypothesis they propose to examine whether impairment of skeletal muscle glucose metabolism (e.g., glycolysis) precedes decreases in insulin's action on glucose transport during chronic development of insulin resistance with high fat feeding in rats. In addition, they propose to examine whether acute suppression of glucose metabolism in skeletal muscle causes subsequent down regulation of insulin's action on glucose transport during prolonged hyperinsulinemic glucose clamps. The investigators also propose to investigate the hexosamine biosynthesis pathway, recently discovered to regulate insulin action in cultured fat cells, as a potential mechanism to link impaired glucose metabolism to the modulation of insulin action in skeletal muscle. Finally, if the role of the hexosamine pathway is established in skeletal muscle, they propose to examine whether feeding rats with diets containing glucosamine results in insulin resistance by increasing the flux through the hexosamine pathway, and if so, whether insulin resistance causes subsequent development of hyperglycemia and/or impaired insulin secretion. This study will provide insights into the mechanisms of development of insulin resistance in skeletal muscle, which is one of the primary events in the pathogenesis of NIDDM.