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: 7217928
• 负责人: Guenther Boden
• 金额: $ 35.68万
• 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 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217928
• 关键词: 1,2-diacylglycerol; 1-Phosphatidylinositol 3-Kinase; Acute; Atherosclerosis; Biopsy; Blood specimen; Cell Adhesion Molecules; Chronic; Data; Development; Diglycerides; Dyslipidemias; Elevation; Enzymes; Fatty acid glycerol esters; Heparin; Hepatic; Hormones; Human; Hypertension; I Kappa B-Alpha; I-kappa B Proteins; IkappaB kinase; Inflammatory; Infusion procedures; Insulin; Insulin Resistance; Link; Lipids; Measurement; Muscle; NF-kappa B; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; PKC-betaII; Pathogenesis; Pathway interactions; Patients; Peripheral; Phosphotransferases; Plasma; Protein Kinase C; Protein-Serine-Threonine Kinases; Relative (related person); Risk Factors; Rodent; Serine; Testing; Time; Tyrosine Phosphorylation; base; citrate carrier; cytokine; diabetic; healthy volunteer; human subject; inhibitor/antagonist; insulin receptor substrate 1 protein; volunteer

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)： 肥胖和其他几个动脉粥样硬化性血管疾病(ASVD)的危险因素，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，尽管IR和ASVD之间的联系的本质仍不清楚，但人们怀疑IR是ASVD发病机制中的一个重要因素。有证据表明，大多数肥胖者血浆游离脂肪酸(FFAs)升高，而血浆FFAs的急性和慢性升高会导致IR，游离脂肪酸(FFA)已被确定为肥胖和IR之间的主要联系。最近的数据表明，FFA诱导的IR伴随着脂肪和二酰甘油(IMCL FFA再酯化为脂肪的副产物)在肌内的积累，通过激活蛋白激酶C(PKC)Beta II和Delta(已知由DAG激活并导致啮齿动物IR的丝氨酸激酶)以及IMCL IkappaB-α的急剧(70%)减少(已知的NFkappaB途径的抑制物，已知的NFkappaB途径是强烈的促炎和致动脉粥样硬化的)。我们建议通过检验下列假设来加强FFA诱导的IR和ASVD之间的假定联系：1)FFA诱导的人肌肉中丝氨酸激酶PKCβII和Delta的激活，或许是IkappaB激酶(IKK)的激活与胰岛素刺激的IRS-1及其相关的PI3激酶的酪氨酸磷酸化降低有关；2)这些变化在IR的发生之前；3)IkappaB-α的减少导致NFkappaB的激活；4)PKC和IKK参与了IR的产生和IkappaB/NFkappaB通路的激活；5)在健康志愿者中，同样的操作机制也适用于T2 DM患者。我们将在正常志愿者和糖尿病志愿者身上测试这些假设，方法是在有或没有联合输注脂质和肝素的情况下进行正常血糖-高胰岛素钳夹(以提高游离脂肪酸)，并通过获取连续的肌肉活组织和血液样本。我们相信，这些研究将提供有关肥胖和游离脂肪酸导致人体IR和ASVD的机制的重要新信息。

项目成果

Comparison of in vivo effects of insulin on SREBP-1c activation and INSIG-1/2 in rat liver and human and rat adipose tissue.

胰岛素对大鼠肝脏，人和大鼠脂肪组织中胰岛素对SREBP-1C激活和Insig-1/2的体内影响的比较。

• DOI: 10.1002/oby.20134
• 发表时间: 2013-06
• 期刊: OBESITY
• 影响因子: 6.9
• 作者: Boden, Guenther;Salehi, Sajad;Cheung, Peter;Homko, Carol;Song, Weiwei;Loveland-Jones, Catherine;Jayarajan, Senthil
• 通讯作者: Jayarajan, Senthil