Fat Induced Insulin Resistance and Atherosclerosis

描述（由申请人提供）： 肥胖和动脉粥样硬化性血管疾病（ASVD）的其他几个危险因素，包括高血压、血脂异常和2型糖尿病，与胰岛素抵抗（IR）有关。因此，人们怀疑IR是ASVD发病机制中的一个重要因素，尽管IR和ASVD之间联系的性质仍然难以捉摸。游离脂肪酸（Free Fatty Acids，FFA）是肥胖和IR之间的主要联系，有证据表明大多数肥胖者血浆FFA水平升高，急性和慢性血浆FFA水平升高可导致IR。最近的数据表明，FFA诱导的IR伴随着脂肪和甘油二酯的肌内（IMCL）积聚（DAG，IMCL FFA再酯化为脂肪的副产物）通过激活蛋白激酶C（PKC）β II和δ（已知被DAG激活并在啮齿动物中引起IR的丝氨酸激酶）和IMCL IkappaB-α的急剧（70%）降低，（NF κ B通路的抑制剂，已知其具有强烈的促炎性和致动脉粥样硬化性）。我们建议通过验证以下假设来加强FFA诱导的IR和ASVD之间的这种假定联系：1）FFA诱导的丝氨酸激酶PKC β II和δ以及可能的人肌肉中的IkappaB激酶（IKK）的激活与胰岛素刺激的IRS-1和IRS-1相关的PI 3激酶的酪氨酸磷酸化的减少有关; 2）这些变化先于IR的发展; 3）IkappaB-α的降低导致NF κ B的活化; 4）PKC和IKK参与IR的产生和IkappaB/NF κ B通路的活化; 5）在健康志愿者中起作用的相同机制也在T2 DM患者中起作用。我们将在正常志愿者和糖尿病志愿者中通过进行正常血糖-高胰岛素钳夹（有或无脂质加肝素共输注）（以提高FFA）以及通过获得连续肌肉活检和血液样本来测试这些假设。我们相信，这些研究将提供重要的新的信息，肥胖和FFA导致IR和ASVD的人类受试者的机制。

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.