Muscle Glucose Metabolism in Diabetes and Exercise

糖尿病和运动中的肌肉葡萄糖代谢

• 批准号: 6970023
• 负责人: GERALD Lynis DOHM
• 金额: $ 29.13万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6970023
• 关键词: biological signal transduction; biopsy; clinical research; diabetes mellitus; enzyme activity; enzyme inhibitors; exercise; gene targeting; genetically modified animals; glucose clamp technique; glucose metabolism; human subject; hyperinsulinism; insulin receptor; insulin sensitivity /resistance; laboratory mouse; lipids; muscle metabolism; obesity; phosphoproteins; phosphorylation; polymerase chain reaction; protein kinase C; western blottings

DESCRIPTION (provided by applicant): Insulin resistance is a co-morbidity of obesity and is a risk factor for the development of type-2 diabetes and cardiovascular disease. We, and others, have demonstrated that there is a relationship between accumulated muscle lipids and insulin resistance. Therefore, the focus of this project is two fold: (1) to investigate the mechanism that causes lipids to accumulate in muscle of obese individuals and (2) to investigate the mechanism that links muscle lipids to disregulation of insulin signal transduction. Our hypothesis is that lipids accumulate (e.g. fatty acyl CoAs, diacylglycerols and/or ceramide) in muscle of insulin resistant individuals because of increased uptake of fatty acids across the cell membrane. The accumulated lipids then activate PKC, which leads to the phosphorylation and inactivation of insulin receptors and IRS-1, and insulin resistance. In specific aim 1 we will continue to investigate whether fatty acid transport and expression of fatty acid transporters are altered in muscle of obese individuals. We will use in vivo studies (e.g. hyperinsulinemic clamp) with muscle biopsies or in vitro experiments with the incubated muscle fiber strip preparation, followed by preparation of giant membrane vesicles, to determine if there are alterations in the membrane distribution of fatty acid transporters with obesity (specific aim 2). In specific aim 3 we plan to use cultured muscle myotubes from lean and obese patients to investigate whether manipulating fatty acid transport will alter accumulation of intracellular lipid and insulin signaling. To investigate the link between lipids and insulin signal transduction, we will use our incubated muscle strip preparation to acutely alter the accumulation of muscle lipids and determine if there are accompanying changes in activation of PKC and phosphorylation of insulin receptors and IRS-1 that are consistent with our hypothesis (specific aim 4). The results of the proposed studies should provide valuable information about the causes and possible treatments of insulin resistance and diabetes.

描述（由申请人提供）：胰岛素抵抗是肥胖的合并症，是2型糖尿病和心血管疾病发展的危险因素。我们和其他人已经证明，累积的肌肉脂质与胰岛素抵抗之间存在关系。因此，该项目的重点是两个方面：（1）研究导致脂质在肥胖个体肌肉中积累的机制，以及（2）研究将肌肉脂质与毫无胰岛素信号转导的机制联系起来的机制。我们的假设是，脂质在胰岛素抵抗个体的肌肉中积累（例如脂肪酰基COA，二酰基甘油和/或神经酰胺），因为整个细胞膜摄入脂肪酸的摄取增加，脂质。然后，累积的脂质激活PKC，这导致胰岛素受体和IRS-1的磷酸化和失活以及胰岛素抵抗。在特定目标1中，我们将继续研究肥胖个体肌肉中脂肪酸转运蛋白的转运和表达是否改变。我们将使用肌肉活检或与孵化的肌肉纤维条制备进行体内研究（例如高胰岛素夹）或体外实验，然后进行巨大的膜囊泡的制备，以确定脂肪酸转运蛋白的膜分布是否发生变化（特定的AIM 2）。在特定目标3中，我们计划使用瘦肉和肥胖患者的培养肌肉肌管，以调查操纵脂肪酸转运是否会改变细胞内脂质和胰岛素信号传导的积累。为了研究脂质与胰岛素信号转导之间的联系，我们将使用孵化的肌肉条制剂来急性改变肌肉脂质的积累，并确定PKC激活的激活和胰岛素受体受体和IRS-1的磷酸化是否存在与我们的假设一致的变化（特定的AIM 4）。拟议研究的结果应提供有关胰岛素抵抗和糖尿病的原因和可能治疗的宝贵信息。