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）：

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