Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade

To examine the mechanism by which free fatty acids (FFAs) induce insulin re sistance in vivo, awake chronically catheterized rats underwent a hyperinsu linemic-euglycemic clamp with or without a 5-h preinfusion of lipid/heparin to raise plasma FFA concentrations. Increased plasma FFAs resulted in insu lin resistance as reflected by a similar to 35% reduction in the glucose in fusion rate (P < 0.05 vs. control). The insulin resistance was associated w ith a 40-50% reduction in C-13 nuclear magnetic resonance (NMR)-determined rates of muscle glycogen synthesis (P < 0.01 vs, control) and muscle glucos e oxidation (P < 0.01 vs. control), which in turn could be attributed to a similar to 25% reduction in glucose transport activity as assessed by 2-[1, 2-H-3]deoxyglucose uptake in vivo (P < 0.05 vs. control). This lipid-induce d decrease in insulin-stimulated muscle glucose metabolism was associated w ith 1) a similar to 50% reduction in insulin-stimulated insulin receptor su bstrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity (P < 0.05 vs. control), 3) a blunting in insulin-stimulated IRS-1 tyrosine phos phorylation (P < 0.05, lipid-infused versus glycerol-infused), and 3) a fou rfold increase in membrane-bound, or active, protein kinase C (PKC) theta ( P < 0.05 vs. control). me conclude that acute elevations of plasma FFA leve ls for 5 h induce skeletal muscle insulin resistance in vivo via a reductio n in insulin-stimulated muscle glycogen synthesis and glucose oxidation tha t can be attributed to reduced glucose transport activity. These changes ar e associated with abnormalities in the insulin signaling cascade and may be mediated by FFA activation of PKC theta.