MECHANISMS OF INSULIN RESISTANCE IN SKELETAL MUSCLE

描述：胰岛素抵抗是非胰岛素抵抗的一个重要风险因素。 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 与许多健康问题的显著关联， 潜在的胰岛素抵抗尚不清楚。 长 研究人员研究的长期目标是阐明 胰岛素抵抗在骨骼肌中发展的细胞机制 肌肉是胰岛素介导葡萄糖的主要组织 摄取。 在本申请中，研究人员建议测试 假设在胰岛素抵抗的发展过程中， 骨骼肌细胞内的葡萄糖代谢先于 导致胰岛素对葡萄糖转运的作用受损。 的 胰岛素对葡萄糖的作用降低的假设的含义 转运（或摄取）是肌肉的次级适应性反应 以防止底物的积累，当其对葡萄糖的能力 为了验证这一假设，他们建议检查 骨骼肌葡萄糖代谢的损伤（例如， 糖酵解）先于胰岛素对葡萄糖转运作用的降低 在高脂血症的胰岛素抵抗慢性发展过程中， 喂养老鼠 此外，他们建议审查是否急性 抑制骨骼肌中的葡萄糖代谢导致随后的 胰岛素对葡萄糖转运作用的下调 长时间高胰岛素葡萄糖钳夹。 调查人员还 建议研究己糖胺生物合成途径，最近 发现在培养的脂肪细胞中调节胰岛素的作用， 潜在的机制，将受损的葡萄糖代谢与 调节骨骼肌中的胰岛素作用。 最后，如果角色 在骨骼肌中建立了己糖胺途径， 建议研究用含有以下成分的食物喂养老鼠 葡萄糖胺通过增加胰岛素的通量而导致胰岛素抵抗 如果是的话，胰岛素抵抗是否 导致随后发生高血糖症和/或胰岛素受损 分泌物 这项研究将提供深入了解的机制， 骨骼肌胰岛素抵抗的发展，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.