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 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.

[1]  E. Kraegen,et al.  Five-hour fatty acid elevation increases muscle lipids and impairs glycogen synthesis in the rat. , 1998, Metabolism: clinical and experimental.

[2]  Y. Yazaki,et al.  Altered Expression Levels and Impaired Steps in the Pathway to Phosphatidylinositol 3-Kinase Activation via Insulin Receptor Substrates 1 and 2 in Zucker Fatty Rats , 1998, Diabetes.

[3]  T. Imamura,et al.  Fatty acid induced insulin resistance in rat-1 fibroblasts overexpressing human insulin receptors: impaired insulin-stimulated mitogen-activated protein kinase activity , 1997, Diabetologia.

[4]  G. Shulman,et al.  13C and 31P NMR Studies on the Effects of Increased Plasma Free Fatty Acids on Intramuscular Glucose Metabolism in the Awake Rat* , 1997, The Journal of Biological Chemistry.

[5]  J. Zierath,et al.  Insulin Receptor Substrate-1 Phosphorylation and Phosphatidylinositol 3-Kinase Activity in Skeletal Muscle From NIDDM Subjects After In Vivo Insulin Stimulation , 1997, Diabetes.

[6]  E. Kraegen,et al.  Alterations in the Expression and Cellular Localization of Protein Kinase C Isozymes ε and θ Are Associated With Insulin Resistance in Skeletal Muscle of the High-Fat–Fed Rat , 1997, Diabetes.

[7]  K. Petersen,et al.  Mechanism of free fatty acid-induced insulin resistance in humans. , 1996, The Journal of clinical investigation.

[8]  F. Giorgino,et al.  Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. , 1995, The Journal of clinical investigation.

[9]  L. Rossetti,et al.  Mechanisms of fatty acid-induced inhibition of glucose uptake. , 1994, The Journal of clinical investigation.

[10]  J. Zierath,et al.  Elevated free fatty acid levels inhibit glucose phosphorylation in slow-twitch rat skeletal muscle. , 1994, Acta physiologica Scandinavica.

[11]  T. Okada,et al.  Essential role of phosphatidylinositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin. , 1994, The Journal of biological chemistry.

[12]  L. Mandarino,et al.  Interaction between glucose and free fatty acid metabolism in human skeletal muscle. , 1993, The Journal of clinical investigation.

[13]  K. Frayn Insulin resistance and lipid metabolism , 1993 .

[14]  M. Mozzoli,et al.  Effects of fat on insulin-stimulated carbohydrate metabolism in normal men. , 1991, The Journal of clinical investigation.

[15]  Y. Le Marchand-Brustel,et al.  Lipid-induced insulin resistance in cultured hepatoma cells is associated with a decreased insulin receptor tyrosine kinase activity. , 1991, Cell regulation.

[16]  L. Cantley,et al.  Activation of phosphatidylinositol 3-kinase by insulin. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Yii-Der I. Chen,et al.  Measurement of Plasma Glucose, Free Fatty Acid, Lactate, and Insulin for 24 h in Patients With NIDDM , 1988, Diabetes.

[18]  D. James,et al.  Dose-response curves for in vivo insulin sensitivity in individual tissues in rats. , 1985, The American journal of physiology.

[19]  M. Vranic,et al.  Resistance to Insulin but Not to Glucagon in Lean Human Hypertriglyceridemics , 1980, Diabetes.

[20]  P. J. Randle,et al.  THE GLUCOSE FATTY ACID CYCLE IN OBESITY AND MATURITY ONSET DIABETES MELLITUS , 1965, Annals of the New York Academy of Sciences.

[21]  E. Newsholme,et al.  The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. , 1963, Lancet.