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

Abstract

To examine the mechanism by which free fatty acids (FFAs) induce insulin resistance in vivo, awake chronically catheterized rats underwent a hyperinsulinemic-euglycemic clamp with or without a 5-h preinfusion of lipid/heparin to raise plasma FFA concentrations. Increased plasma FFAs resulted in insulin resistance as reflected by a approximately 35% reduction in the glucose infusion rate (P < 0.05 vs. control). The insulin resistance was associated with a 40-50% reduction in 13C nuclear magnetic resonance (NMR)-determined rates of muscle glycogen synthesis (P < 0.01 vs. control) and muscle glucose oxidation (P < 0.01 vs. control), which in turn could be attributed to a approximately 25% reduction in glucose transport activity as assessed by 2-[1,2-3H]deoxyglucose uptake in vivo (P < 0.05 vs. control). This lipid-induced decrease in insulin-stimulated muscle glucose metabolism was associated with 1) a approximately 50% reduction in insulin-stimulated insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity (P < 0.05 vs. control), 2) a blunting in insulin-stimulated IRS-1 tyrosine phosphorylation (P < 0.05, lipid-infused versus glycerol-infused), and 3) a four-fold increase in membrane-bound, or active, protein kinase C (PKC) theta (P < 0.05 vs. control). We conclude that acute elevations of plasma FFA levels for 5 h induce skeletal muscle insulin resistance in vivo via a reduction in insulin-stimulated muscle glycogen synthesis and glucose oxidation that can be attributed to reduced glucose transport activity. These changes are associated with abnormalities in the insulin signaling cascade and may be mediated by FFA activation of PKC theta.

Human triglyceride-rich lipoproteins impair glucose metabolism and insulin signalling in L6 skeletal muscle cells independently of non-esterified fatty acid levels

“…The rise in plasma levels of NEFAs has been shown to induce insulin resistance [5][6][7][8]. In line with these studies, it has been demonstrated that CD36 knockout mice have improved insulin sensitivity in muscle, implying that fatty acid flux into the cells plays a critical role in insulin resistance [9].…”

Effect of α-tocopherol and β-carotene supplementation on the incidence of type 2 diabetes

“…The antioxidant property of vitamin E is often considered a key activity, although vitamin E does cause other effects that could potentially modify the action of insulin. For example, vitamin E inhibits protein kinase C activity, which has been associated with insulin resistance experimentally [19]. Vitamin E regulates several genes; for example, it upregulates the expression of PPARG, the gene for peroxisome proliferator activated receptor γ (PPARγ) [20].…”

Lipid signalling in disease

“…Mounting evidence indicates that activation of c-Jun N-terminal kinase (JNK), IKK and conventional PKC is central to the development of insulin resistance in response to obesity -mediated by the aforementioned fatty acidinduced ER stress, ROS production, TLR activation and inflammatory signalling by TNF . JNK, IKK and PKC have all been reported to inhibit insulin action by phosphorylating IRS1 on serine [80][81][82] . Serine phosphorylation of IRS1 disrupts insulin-receptor signalling through several distinct mechanisms and blocks insulin action 83,84 .…”