Role of Fatty Acids in the Pathogenesis of Insulin Resistance and NIDDM

Evidence is reviewed that free fatty acids (FFAs) are one important link between obesity and insulin resistance and NIDDM. First, plasma FFA levels are elevated in most obese subjects. Second, physiological elevations in plasma FFA concentrations inhibit insulin stimulated peripheral glucose uptake in a dose-dependent manner in normal controls and in patients with NIDDM. Two possible mechanisms are identified: 1) a fat-related inhibition of glucose transport or phosphorylation, which appears after 3–4 h of fat infusion, and 2) a decrease in muscle glycogen synthase activity, which appears after 4–6 h of fat infusion. Third, FFAs stimulate insulin secretion in nondiabetic individuals. Some of this insulin is transmitted in the peripheral circulation and is able to compensate for FFA-mediated peripheral insulin resistance. FFA-mediated portal hyperinsulinemia counteracts the stimulation of FFAs on hepatic glucose production (HGP) and thus prevents hepatic glucose overproduction. We speculate that, in obese individuals who are genetically predisposed to develop NIDDM, FFAs will eventually fail to promote insulin secretion. The stimulatory effect of FFAs on HGP would then become unchecked, resulting in hyperglycemia. Hence, continuously elevated levels of plasma FFAs may play a key role in the pathogenesis of NIDDM in predisposed individuals by impairing peripheral glucose utilization and by promoting hepatic glucose overproduction.

[1]  G. Assmann,et al.  The Prospective Cardiovascular Münster (PROCAM) study: prevalence of hyperlipidemia in persons with hypertension and/or diabetes mellitus and the relationship to coronary heart disease. , 1988, American heart journal.

[2]  B V Howard,et al.  Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. , 1988, The New England journal of medicine.

[3]  E. Jéquier,et al.  Impairment of glucose disposal by infusion of triglycerides in humans: role of glycemia. , 1989, The American journal of physiology.

[4]  E. Ferrannini,et al.  Operation of Randle's Cycle in Patients With NIDDM , 1990, Diabetes.

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

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

[7]  W. Malaisse,et al.  Stimulation of insulin secretion by noncarbohydrate metabolites. , 1968, The Journal of laboratory and clinical medicine.

[8]  Yun-ping Zhou,et al.  Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. , 1994, The Journal of clinical investigation.

[9]  B. Spiegelman,et al.  Reduced tyrosine kinase activity of the insulin receptor in obesity-diabetes. Central role of tumor necrosis factor-alpha. , 1994, The Journal of clinical investigation.

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

[11]  L. Sjöström,et al.  Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution. , 1983, The Journal of clinical investigation.

[12]  V. Grill,et al.  A 48-hour lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation. , 1990, Endocrinology.

[13]  R. Unger,et al.  Defective Fatty Acid-mediated -Cell Compensation in Zucker Diabetic Fatty Rats , 1996, The Journal of Biological Chemistry.

[14]  F. Matschinsky,et al.  Mechanisms of action of nonglucose insulin secretagogues. , 1994, Annual review of nutrition.

[15]  A. Vaag,et al.  Effect of the antilipolytic nicotinic acid analogue acipimox on whole-body and skeletal muscle glucose metabolism in patients with non-insulin-dependent diabetes mellitus. , 1991, The Journal of clinical investigation.

[16]  D. Kipnis,et al.  Effects of fatty acids on carbohydrate and fatty acid metabolism of rat diaphragm. , 1968, The American journal of physiology.

[17]  H. Yki-Järvinen,et al.  Inhibition of Lipolysis Decreases Lipid Oxidation and Gluconeogenesis From Lactate But Not Fasting Hyperglycemia or Total Hepatic Glucose Production in NIDDM , 1993, Diabetes.

[18]  R. Hanson,et al.  Regulation of hepatic gluconeogenesis in the guinea pig by fatty acids and ammonia. , 1975, The Journal of biological chemistry.

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

[20]  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.

[21]  G. Boden,et al.  Effects of a 48-h Fat Infusion on Insulin Secretion and Glucose Utilization , 1995, Diabetes.

[22]  Y. Gotō,et al.  Influence of the World War II Food Shortage on the Incidence of Diabetes Mellitus in Japan , 1958, Diabetes.

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

[24]  G. Boden,et al.  Effects of Lipid on Basal Carbohydrate Metabolism in Normal Men , 1991, Diabetes.

[25]  R. Bergman,et al.  Free Fatty Acid as a Link in the Regulation of Hepatic Glucose Output by Peripheral Insulin , 1995, Diabetes.

[26]  B. Spiegelman,et al.  Tumor Necrosis Factor α: A Key Component of the Obesity-Diabetes Link , 1994, Diabetes.

[27]  G. Boden,et al.  Effects of prolonged glucose infusion on insulin secretion, clearance, and action in normal subjects. , 1996, The American journal of physiology.

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

[29]  M. Taskinen,et al.  Effect of Acute Elevation of Plasma Glycerol, Triglyceride and FFA Levels on Glucose Utilization and Plasma Insulin , 1968, Diabetes.

[30]  D. Chisholm,et al.  The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids. , 1993, The New England journal of medicine.

[31]  R. Mueller,et al.  Splanchnic insulin metabolism in obesity. Influence of body fat distribution. , 1986, The Journal of clinical investigation.

[32]  M. Walker,et al.  Metabolic Effects of Suppression of Nonesterified Fatty Acid Levels With Acipimox in Obese NIDDM Subjects , 1992, Diabetes.

[33]  L. Storlien,et al.  Inducement by Fat Feeding of Basal Hyperglycemia in Rats With Abnormal β-Cell Function: Model for Study of Etiology and Pathogenesis of NIDDM , 1990, Diabetes.

[34]  C. Kahn,et al.  Maintenance of 3T3-L1 cells in culture media containing saturated fatty acids decreases insulin binding and insulin action. , 1981, Biochemical and biophysical research communications.

[35]  E. Gordon Non-Esterified Fatty Acids in the Blood of Obese and Lean Subjects , 1960 .

[36]  J. Williamson,et al.  Control mechanisms of gluconeogenesis and ketogenesis. I. Effects of oleate on gluconeogenesis in perfused rat liver. , 1969, The Journal of biological chemistry.

[37]  G. Boden,et al.  Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes. , 1995, The Journal of clinical investigation.

[38]  R. Farías Insulin-membrane interactions and membrane fluidity changes. , 1987, Biochimica et biophysica acta.

[39]  M. Buse,et al.  Pre-Exposure to Glucosamine Induces Insulin Resistance of Glucose Transport and Glycogen Synthesis in Isolated Rat Skeletal Muscles: Study of Mechanisms in Muscle and in Rat-1 Fibroblasts Overexpressing the Human Insulin Receptor , 1993, Diabetes.

[40]  R. DeFronzo,et al.  Time dependence of the interaction between lipid and glucose in humans. , 1989, The American journal of physiology.

[41]  C. Morand,et al.  Fatty acids are potent modulators of lactate utilization in isolated hepatocytes from fed rats. , 1993, The American journal of physiology.

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

[43]  P. Pekala,et al.  Regulation of GLUT4 Gene Expression by Arachidonic Acid , 1996, The Journal of Biological Chemistry.

[44]  W. Tamborlane,et al.  Interstitial fluid concentrations of glycerol, glucose, and amino acids in human quadricep muscle and adipose tissue. Evidence for significant lipolysis in skeletal muscle. , 1995, The Journal of clinical investigation.

[45]  M. Jensen,et al.  Influence of body fat distribution on free fatty acid metabolism in obesity. , 1989, The Journal of clinical investigation.

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

[47]  L. Groop,et al.  Demonstration of a novel feedback mechanism between FFA oxidation from intracellular and intravascular sources. , 1991, The American journal of physiology.

[48]  A. Vaag,et al.  Pronounced blood glucose-lowering effect of the antilipolytic drug acipimox in noninsulin-dependent diabetes mellitus patients during a 3-day intensified treatment period. , 1994, The Journal of clinical endocrinology and metabolism.

[49]  R. Parrilla,et al.  Control of hepatic gluconeogenesis: role of fatty acid oxidation. , 1989, Archives of biochemistry and biophysics.

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

[51]  R. Unger Lipotoxicity in the Pathogenesis of Obesity-Dependent NIDDM: Genetic and Clinical Implications , 1995, Diabetes.

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

[53]  T. van der Poll,et al.  Tumor necrosis factor mimics the metabolic response to acute infection in healthy humans. , 1991, The American journal of physiology.

[54]  E. Pfeiffer,et al.  Action of B-Hydroxy Butyrate, Acetoacetate and Palmitate on the Insulin Release in the Perfused Isolated Rat Pancreas* , 1974, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[55]  A. A. Spector,et al.  Effect of the Membrane Lipid Environment on the Properties of Insulin Receptors , 1981, Diabetes.

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

[57]  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.

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

[59]  S. Marshall,et al.  Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. , 1991, The Journal of biological chemistry.

[60]  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.

[61]  R. Cassens,et al.  Effect of octanoate on carbohydrate metabolism in red and white muscle of the rhesus monkey. , 1969, The American journal of physiology.

[62]  E. A. Sims,et al.  Endocrine and metabolic effects of experimental obesity in man. , 1973, Recent progress in hormone research.

[63]  C. H. Beatty,et al.  Interrelation of carbohydrate and palmitate metabolism in skeletal muscle. , 1971, The American journal of physiology.

[64]  D. Steinberg,et al.  Stimulation of insulin secretion by long-chain free fatty acids. A direct pancreatic effect. , 1973, The Journal of clinical investigation.

[65]  N. Ruderman,et al.  Glucose Metabolism in Rat Skeletal Muscle at Rest: Effect of Starvation, Diabetes, Ketone Bodies and Free Fatty Acids , 1974, Diabetes.

[66]  S. Marshall,et al.  Recovery of maximal insulin responsiveness and insulin sensitivity after induction of insulin resistance in primary cultured adipocytes. , 1989, The Journal of biological chemistry.

[67]  A. Vannotti,et al.  EFFECTS OF FAT INFUSION ON GLUCOSE TOLERANCE AND INSULIN PLASMA LEVELS. , 1964, Medicina experimentalis : International journal of experimental medicine.

[68]  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.