Mechanisms of fatty acid-induced inhibition of glucose uptake.

Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels (approximately 50, approximately 550, approximately 750 microM) on rates of glucose uptake, glycolysis (both with 3-3H-glucose), glycogen synthesis (determined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA concentration (from approximately 50 to approximately 750 microM) decreased glucose uptake in a dose-dependent fashion (from approximately 9 to approximately 4 mg/kg per min). The decrease was caused mainly (approximately 2/3) by a reduction in glycogen synthesis and to a lesser extent (approximately 1/3) by a reduction in CHO oxidation. We have identified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activity. It required high FFA concentration (approximately 750 microM), was associated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium (approximately 550 microM) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by approximately 50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level.

[1]  G. Boden,et al.  Effects of oleate and fatty acids from omental adipocytes on insulin uptake in rat liver cells. , 1993, Endocrinology.

[2]  H. Shamoon,et al.  Quantitation of glycolysis and skeletal muscle glycogen synthesis in humans. , 1993, The American journal of physiology.

[3]  P. Brunetti,et al.  Demonstration of a critical role for free fatty acids in mediating counterregulatory stimulation of gluconeogenesis and suppression of glucose utilization in humans. , 1993, The Journal of clinical investigation.

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

[5]  R. Taylor,et al.  Abnormal Activation of Glycogen Synthesis in Fibroblasts from NIDDM Subjects: Evidence for an Abnormality Specific to Glucose Metabolism , 1993, Diabetes.

[6]  L. Groop,et al.  Contribution of muscle and liver to glucose-fatty acid cycle in humans. , 1993, The American journal of physiology.

[7]  L. Rossetti,et al.  Multiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase. , 1993, The American journal of physiology.

[8]  R. DeFronzo,et al.  The Metabolic Profile of NIDDM Is Fully Established in Glucose-Tolerant Offspring of Two Mexican-American NIDDM Parents , 1992, Diabetes.

[9]  J. McGarry,et al.  What if Minkowski had been ageusic? An alternative angle on diabetes. , 1992, Science.

[10]  A. Vaag,et al.  Decreased insulin activation of glycogen synthase in skeletal muscles in young nonobese Caucasian first-degree relatives of patients with non-insulin-dependent diabetes mellitus. , 1992, The Journal of clinical investigation.

[11]  R. DeFronzo,et al.  Pathogenesis of NIDDM: A Balanced Overview , 1992, Diabetes Care.

[12]  L. Mandarino,et al.  Skeletal muscle is a major site of lactate uptake and release during hyperinsulinemia. , 1992, Metabolism: clinical and experimental.

[13]  R. DeFronzo,et al.  The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. , 1992, Diabetes.

[14]  O. Pedersen,et al.  Impaired Expression of Glycogen Synthase mRNA in Skeletal Muscle of NIDDM Patients , 1991, Diabetes.

[15]  J. Holloszy,et al.  Palmitate stimulates glucose transport in rat adipocytes by a mechanism involving translocation of the insulin sensitive glucose transporter (GLUT4). , 1991, Biochemical and biophysical research communications.

[16]  R. Henry,et al.  Multiple defects in muscle glycogen synthase activity contribute to reduced glycogen synthesis in non-insulin dependent diabetes mellitus. , 1991, The Journal of clinical investigation.

[17]  L. Groop,et al.  Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man. , 1991, The Journal of clinical investigation.

[18]  A. Consoli,et al.  Mechanism of increased gluconeogenesis in noninsulin-dependent diabetes mellitus. Role of alterations in systemic, hepatic, and muscle lactate and alanine metabolism. , 1990, The Journal of clinical investigation.

[19]  L. Mandarino,et al.  Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in noninsulin-dependent diabetes mellitus. , 1990, The Journal of clinical investigation.

[20]  R. Taylor,et al.  Effects of Intensive Dietary Treatment on Insulin‐stimulated Skeletal Muscle Glycogen Synthase Activation and Insulin Secretion in Newly Presenting Type 2 Diabetic Patients , 1990, Diabetic medicine : a journal of the British Diabetic Association.

[21]  L. Rossetti,et al.  Relative contribution of glycogen synthesis and glycolysis to insulin-mediated glucose uptake. A dose-response euglycemic clamp study in normal and diabetic rats. , 1990, The Journal of clinical investigation.

[22]  E. Ferrannini,et al.  Effects of Insulin on Hemodynamics and Metabolism in Human Forearm , 1990, Diabetes.

[23]  R G Shulman,et al.  Quantitation of muscle glycogen synthesis in normal subjects and subjects with non-insulin-dependent diabetes by 13C nuclear magnetic resonance spectroscopy. , 1990, The New England journal of medicine.

[24]  A. Baron,et al.  Use of a variable tracer infusion method to determine glucose turnover in humans. , 1990, The American journal of physiology.

[25]  E. Ferrannini,et al.  Effects of insulin on hemodynamics and metabolism in human forearm. , 1990, Diabetes.

[26]  L. Rossetti,et al.  Correction of chronic hyperglycemia with vanadate, but not with phlorizin, normalizes in vivo glycogen repletion and in vitro glycogen synthase activity in diabetic skeletal muscle. , 1989, The Journal of clinical investigation.

[27]  L. Groop,et al.  Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. , 1989, The New England journal of medicine.

[28]  B. Hansen,et al.  Mechanisms limiting glycogen storage in muscle during prolonged insulin stimulation. , 1988, The American journal of physiology.

[29]  L. Tappy,et al.  Effect of Hyperinsulinemia on Urea Pool Size and Substrate Oxidation Rates , 1988, Diabetes.

[30]  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.

[31]  R. Wolfe,et al.  Effect of elevated free fatty acids on glucose oxidation in normal humans. , 1988, Metabolism: clinical and experimental.

[32]  E. Ferrannini,et al.  Acute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects. , 1987, Metabolism: clinical and experimental.

[33]  N. Nurjhan,et al.  Insulin Dose-Response Characteristics for Suppression of Glycerol Release and Conversion to Glucose in Humans , 1986, Diabetes.

[34]  O. Owen,et al.  In vivo and in vitro effects of antiinsulin receptor antibodies. , 1984, The Journal of clinical endocrinology and metabolism.

[35]  O. Owen,et al.  Carbohydrate Oxidation and Storage in Obese Non-insulin-dependent Diabetic Patients: Effects of Improving Glycemic Control , 1983, Diabetes.

[36]  R. DeFronzo,et al.  Effect of fatty acids on glucose production and utilization in man. , 1983, The Journal of clinical investigation.

[37]  R. DeFronzo,et al.  Effect of long chain triglyceride infusion on glucose metabolism in man. , 1982, Metabolism: clinical and experimental.

[38]  R. DeFronzo,et al.  The Effect of Insulin on the Disposal of Intravenous Glucose: Results from Indirect Calorimetry and Hepatic and Femoral Venous Catheterization , 1981, Diabetes.

[39]  O. Owen,et al.  Effects of Therapy on the Nature and Quantity of Fuels Oxidized During Diabetic Ketoacidosis , 1980, Diabetes.

[40]  E. Reimann,et al.  Glycogen synthase activation in human skeletal muscle: effects of diet and exercise. , 1979, The American journal of physiology.

[41]  K. Kim,et al.  Mechanism of palmityl coenzyme A inhibition of liver glycogen synthase. , 1977, The Journal of biological chemistry.

[42]  J. A. Thomas,et al.  A rapid filter paper assay for UDPglucose-glycogen glucosyltransferase, including an improved biosynthesis of UDP-14C-glucose. , 1968, Analytical biochemistry.

[43]  R. Kreisberg,et al.  Mechanism for the stimulation of gluconeogenesis by fatty acids in perfused rat liver. , 1966, Proceedings of the National Academy of Sciences of the United States of America.

[44]  D. Slone,et al.  Critical Variables in the Radioimmunoassay of Serum Insulin Using the Double Antibody Technic , 1965, Diabetes.

[45]  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.

[46]  W. H. Marsh,et al.  AUTOMATED AND MANUAL DIRECT METHODS FOR THE DETERMINATION OF BLOOD UREA. , 1965, Clinical chemistry.

[47]  W. Danforth.  GLYCOGEN SYNTHETASE ACTIVITY IN SKELETAL MUSCLE. INTERCONVERSION OF TWO FORMS AND CONTROL OF GLYCOGEN SYNTHESIS. , 1965, The Journal of biological chemistry.

[48]  D. Strandness,et al.  Mercury strain gauge plethysmography. Evaluation of patients with acquired arteriovenous fistula. , 1962, Archives of surgery.

[49]  R. Steele,et al.  Measurement of size and turnover rate of body glucose pool by the isotope dilution method. , 1956, The American journal of physiology.