Fat Induced Insulin Resistance and Atherosclerosis

The overall objective of the current proposal is to strengthen the putative link between FFA induced insulin resistance and atherosclerotic vascular disease (ASVD). To this end, the investigators will test the following hypotheses: 1) that FFA induced activation of protein kinase C βII (PKC β II) and δ and other serine kinases such as IκB kinase (IKK) in human muscle is associated with a decrease in insulin stimulated tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1) and of IRS-1 associated phosphatidylinositol 3 (PI3) kinase; 2) that these changes precede the development of insulin resistance; 3) that the decrease in IκB-α results in activation of nuclear factor κB (NFκB) and the expression of adhesion molecules and cytokines; 4) that PKC and IKK are involved in producing insulin resistance and activation of the IκB/ NFκB pathway and lastly 5) that the same mechanisms operative in healthy volunteers are also operative in patients with T2DM.The investigators will test these hypotheses in normal (current) and diabetic volunteers (previously completed) . Euglycemic-hyperinsulinemic clamps will be performed with and without co-infusion of lipid plus heparin (to raise FFAs) and by obtaining serial muscle and fat biopsies and blood samples will be obtained for measurement of substrates, hormones, enzymes and metabolites.