Fat Induced Insulin Resistance and Atherosclerosis

脂肪引起的胰岛素抵抗和动脉粥样硬化

• 批准号: 7055288
• 负责人: Guenther Boden
• 金额: $ 36.74万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7055288
• 关键词: I kappa B beta; atherosclerosis; biopsy; cardiovascular disorder risk; clinical research; diacylglycerols; enzyme activity; free fatty acids; glucose clamp technique; human subject; insulin receptor; insulin sensitivity /resistance; muscle metabolism; noninsulin dependent diabetes mellitus; nuclear factor kappa beta; obesity; patient oriented research; phosphatidylinositol 3 kinase; phosphorylation; protein kinase C; serine threonine protein kinase

DESCRIPTION (provided by applicant): Obesity and several other risk factors for atherosclerotic vascular disease (ASVD) including hypertension, dyslipidemia and type 2 diabetes are associated with insulin resistance (IR). It has been suspected, therefore, that IR is an important factor in the pathogenesis of ASVD although the nature of the connection between IR and ASVD has remained elusive. Free fatty acids (FFAs) have been established as a major link between obesity and IR based on evidence showing that most obese people have elevated plasma FFAs and that acute as well as chronic elevation of plasma FFAs cause IR. Recent data have shown that FFA induced IR was accompanied by intramyocellular (IMCL) accumulation of fat and diacylglycerol (DAG, a by-product of IMCL FFA reesterification to fat) by activation of protein kinase C (PKC) Beta II and delta (serine kinases known to be activated by DAG and to cause IR in rodents) and by a drastic (70%) reduction of IMCL IkappaB-alpha, (the inhibitor of the NFkappaB pathway which is known to be strongly pro-inflammatory and atherogenic). We propose to strengthen this putative link between FFA induced IR and ASVD by testing the following hypotheses: 1) that FFA induced activation of the serine kinases PKC beta II and delta and perhaps IkappaB kinase (IKK) in human muscle is associated with a decrease in insulin stimulated tyrosine phosphorylation of IRS-1 and of IRS-1 associated PI3 kinase; 2) that these changes precede the development of IR; 3) that the decrease in IkappaB-alpha results in activation of NFkappaB; 4) that PKC and IKK are involved in producing IR and activation of the IkappaB/NFkappaB pathway and 5) that the same mechanisms operative in healthy volunteers are also operative in patients with T2DM. We will test these hypotheses in normal and diabetic volunteers by performing euglycemic-hyperinsulinemic clamps with and without co-infusion of lipid plus heparin (to raise FFAs) and by obtaining serial muscle biopsies and blood samples. We believe that these studies will provide important new information relative to the mechanism by which obesity and FFAs cause IR and ASVD in human subjects.

描述（由申请人提供）： 肥胖症和其他几种动脉粥样硬化血管疾病（ASVD）（包括高血压，血脂异常和2型糖尿病）的危险因素与胰岛素抵抗（IR）有关。因此，人们怀疑IR是ASVD发病机理的重要因素，尽管IR和ASVD之间的联系的性质仍然难以捉摸。基于证据表明，大多数肥胖者的血浆FFA升高，血浆FFA的急性以及慢性升高引起IR，因此已建立游离脂肪酸（FFA）作为肥胖与IR之间的主要联系。最近的数据表明，FFA诱导的IR伴随着脂肪和二酰基甘油的膜细胞内（IMCL）积累（DAG，DAG，IMCL FFA对脂肪的副产品的副产品），通过激活蛋白激酶C（PKC）Beta II和Delta（通过丝氨酸激酶）激活DAG和IR的蛋白激酶C（PKC）beta酶（PKC）和DAG的Rodents irave Rodents ir（ircy in Ir in Ir in Ir in Ir in Ir），以及IR的重塑（IR）。 ikappab-alpha，（NFKappab途径的抑制剂，已知具有强烈的促炎和动脉粥样硬化）。我们建议通过测试以下假设来加强FFA诱导的IR和ASVD之间的这种推定联系：1）FFA诱导丝氨酸激酶PKC Beta II和Delta和Delta的激活以及人类肌肉在人类肌肉中的激活与胰岛素刺激的酪氨酸胰岛素相关的irs磷酸化和IRS-1的降低有关2）这些变化在IR的发展之前； 3）Ikappab-Alpha的减少导致NFKappab的激活； 4）PKC和IKK参与生产IR和IKAPPAB/NFKAPPAB途径的激活和5）5）在健康志愿者中使用相同的机制在T2DM患者中也是可操作的。我们将通过或不共同输注脂质加肝素（提高FFA）并获得连续的肌肉活检和血液样本来测试正常和糖尿病志愿者中的这些假设。我们认为，这些研究将提供有关肥胖和FFA在人类受试者中引起IR和ASVD的机制的重要新信息。