This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krebs, M. Articles by Roden, M. Search for Related Content PubMed PubMed Citation Articles by Krebs, M. Articles by Roden, M.

Free Fatty Acids Inhibit the Glucose-Stimulated Increase of Intramuscular Glucose-6-Phosphate Concentration in Humans¹

Division of Endocrinology and Metabolism (Mi.K., Ma.K., P.N., D.W., M.B., H.S., C.F., W.W., M.R.), Department of Internal Medicine III, and Institute of Medical Physics (S.G., V.M.), University of Vienna Medical School, A-1090 Vienna, Austria

Address all correspondence and requests for reprints to: Michael Roden, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna Medical School, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: michael.roden{at}akh-wien ac.at.

To test Randle’s hypothesis we examined whether free fatty acids (FFAs) affect glucose-stimulated glucose transport/phosphorylation and allosteric mediators of muscle glucose metabolism under conditions of fasting peripheral insulinemia. Seven healthy men were studied during somatostatin-glucose-insulin clamp tests [plasma insulin, 50 pmol/L; plasma glucose, 5 mmol/L (0–180 min), 10 mmol/L (180–300 min)] in the presence of low (0.05 mmol/L) and increased (2.6 mmol/L) plasma FFA concentrations. ³¹P and ¹H nuclear magnetic resonance spectroscopy was used to determine intracellular concentrations of glucose-6-phosphate (G6P), inorganic phosphate, phosphocreatine, ADP, pH, and intramyocellular lipids. Rates of glucose turnover were measured using D-[6,6-²H₂]glucose. Plasma FFA elevation reduced rates of glucose uptake at the end of the euglycemic period (R_{d 150–180 min}: 8.6 ± 0.5 vs. 12.6 ± 1.6 µmol/kg·min, P < 0.05) and during hyperglycemia (R_{d 270–300 min}: 9.9 ± 0.6 vs. 22.3 ± 1.7 µmol/kg·min, P < 0.01). Similarly, intramuscular G6P was lower at the end of both euglycemic (G6P_{167–180 min}: -22 ± 7 vs. +24 ± 7 µmol/L, P < 0.05) and hyperglycemic periods (G6P_{287–300 min}: -7 ± 9 vs. +28 ± 7 µmol/L, P < 0.05). Changes in intracellular inorganic phosphate exhibited a similar pattern, whereas FFA did not affect phosphocreatine, ADP, pH, and intramyocellular lipid contents. In conclusion, the lack of an increase in muscular G6P along with reduction of whole body glucose clearance indicates that FFA might directly inhibit glucose transport/phosphorylation in skeletal muscle.

This article has been cited by other articles:

				J. Szendroedi, C. Anderwald, M. Krssak, M. Bayerle-Eder, H. Esterbauer, G. Pfeiler, A. Brehm, P. Nowotny, A. Hofer, W. Waldhausl, et al. Effects of High-Dose Simvastatin Therapy on Glucose Metabolism and Ectopic Lipid Deposition in Nonobese Type 2 Diabetic Patients Diabetes Care, February 1, 2009; 32(2): 209 - 214. [Abstract] [Full Text] [PDF]

				M. Promintzer, M. Krebs, J. Todoric, A. Luger, M. G. Bischof, P. Nowotny, O. Wagner, H. Esterbauer, and C. Anderwald Insulin Resistance Is Unrelated to Circulating Retinol Binding Protein and Protein C Inhibitor J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4306 - 4312. [Abstract] [Full Text] [PDF]

				M. Anderwald-Stadler, M. Krebs, M. Promintzer, M. Mandl, M. G. Bischof, P. Nowotny, T. Kastenbauer, A. Luger, R. Prager, and C. Anderwald Plasma obestatin is lower at fasting and not suppressed by insulin in insulin-resistant humans Am J Physiol Endocrinol Metab, November 1, 2007; 293(5): E1393 - E1398. [Abstract] [Full Text] [PDF]

				E. A. Walker, A. Ahmed, G. G. Lavery, J. W. Tomlinson, S. Y. Kim, M. S. Cooper, J. P. Ride, B. A. Hughes, C. H. L. Shackleton, P. McKiernan, et al. 11beta-Hydroxysteroid Dehydrogenase Type 1 Regulation by Intracellular Glucose 6-Phosphate Provides Evidence for a Novel Link between Glucose Metabolism and Hypothalamo-Pituitary-Adrenal Axis Function J. Biol. Chem., September 14, 2007; 282(37): 27030 - 27036. [Abstract] [Full Text] [PDF]

				C. Anderwald, M. Anderwald-Stadler, M. Promintzer, G. Prager, M. Mandl, P. Nowotny, M. G. Bischof, M. Wolzt, B. Ludvik, T. Kastenbauer, et al. The Clamp-Like Index: A novel and highly sensitive insulin sensitivity index to calculate hyperinsulinemic clamp glucose infusion rates from oral glucose tolerance tests in nondiabetic subjects Diabetes Care, September 1, 2007; 30(9): 2374 - 2380. [Abstract] [Full Text] [PDF]

				M. Krebs, B. Brunmair, A. Brehm, M. Artwohl, J. Szendroedi, P. Nowotny, E. Roth, C. Furnsinn, M. Promintzer, C. Anderwald, et al. The Mammalian Target of Rapamycin Pathway Regulates Nutrient-Sensitive Glucose Uptake in Man Diabetes, June 1, 2007; 56(6): 1600 - 1607. [Abstract] [Full Text] [PDF]

				A. Brehm, K. Thomaseth, E. Bernroider, P. Nowotny, W. Waldhausl, G. Pacini, and M. Roden The Role of Endocrine Counterregulation for Estimating Insulin Sensitivity from Intravenous Glucose Tolerance Tests J. Clin. Endocrinol. Metab., June 1, 2006; 91(6): 2272 - 2278. [Abstract] [Full Text] [PDF]

				A. Brehm, M. Krssak, A. I. Schmid, P. Nowotny, W. Waldhausl, and M. Roden Increased Lipid Availability Impairs Insulin-Stimulated ATP Synthesis in Human Skeletal Muscle Diabetes, January 1, 2006; 55(1): 136 - 140. [Abstract] [Full Text] [PDF]

				M. Bajaj, S. Suraamornkul, A. Romanelli, G. W. Cline, L. J. Mandarino, G. I. Shulman, and R. A. DeFronzo Effect of a Sustained Reduction in Plasma Free Fatty Acid Concentration on Intramuscular Long-Chain Fatty Acyl-CoAs and Insulin Action in Type 2 Diabetic Patients Diabetes, November 1, 2005; 54(11): 3148 - 3153. [Abstract] [Full Text] [PDF]

				E. Bernroider, A. Brehm, M. Krssak, C. Anderwald, Z. Trajanoski, G. Cline, G. I. Shulman, and M. Roden The Role of Intramyocellular Lipids during Hypoglycemia in Patients with Intensively Treated Type 1 Diabetes J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5559 - 5565. [Abstract] [Full Text] [PDF]

				F. Tremblay, M. Krebs, L. Dombrowski, A. Brehm, E. Bernroider, E. Roth, P. Nowotny, W. Waldhausl, A. Marette, and M. Roden Overactivation of S6 Kinase 1 as a Cause of Human Insulin Resistance During Increased Amino Acid Availability Diabetes, September 1, 2005; 54(9): 2674 - 2684. [Abstract] [Full Text] [PDF]

				R. T. de Jongh, E. H. Serne, R. G. IJzerman, G. de Vries, and C. D.A. Stehouwer Free Fatty Acid Levels Modulate Microvascular Function: Relevance for Obesity-Associated Insulin Resistance, Hypertension, and Microangiopathy Diabetes, November 1, 2004; 53(11): 2873 - 2882. [Abstract] [Full Text] [PDF]

				S. R. Kashyap, R. Belfort, R. Berria, S. Suraamornkul, T. Pratipranawatr, J. Finlayson, A. Barrentine, M. Bajaj, L. Mandarino, R. DeFronzo, et al. Discordant effects of a chronic physiological increase in plasma FFA on insulin signaling in healthy subjects with or without a family history of type 2 diabetes Am J Physiol Endocrinol Metab, September 1, 2004; 287(3): E537 - E546. [Abstract] [Full Text] [PDF]

				M. Roden How Free Fatty Acids Inhibit Glucose Utilization in Human Skeletal Muscle Physiology, June 1, 2004; 19(3): 92 - 96. [Abstract] [Full Text] [PDF]

				S. R. Stannard and N. A. Johnson Insulin resistance and elevated triglyceride in muscle: more important for survival than 'thrifty' genes? J. Physiol., February 1, 2004; 554(3): 595 - 607. [Abstract] [Full Text] [PDF]

				M. C. Moore, S. Satake, M. Lautz, S. A. Soleimanpour, D. W. Neal, M. Smith, and A. D. Cherrington Nonesterified Fatty Acids and Hepatic Glucose Metabolism in the Conscious Dog Diabetes, January 1, 2004; 53(1): 32 - 40. [Abstract] [Full Text] [PDF]

				M. Hawkins, J. Tonelli, P. Kishore, D. Stein, E. Ragucci, A. Gitig, and K. Reddy Contribution of Elevated Free Fatty Acid Levels to the Lack of Glucose Effectiveness in Type 2 Diabetes Diabetes, November 1, 2003; 52(11): 2748 - 2758. [Abstract] [Full Text] [PDF]

				A. Kautzky-Willer, M. Krssak, C. Winzer, G. Pacini, A. Tura, S. Farhan, O. Wagner, G. Brabant, R. Horn, H. Stingl, et al. Increased Intramyocellular Lipid Concentration Identifies Impaired Glucose Metabolism in Women With Previous Gestational Diabetes Diabetes, February 1, 2003; 52(2): 244 - 251. [Abstract] [Full Text] [PDF]

				H. Stingl, W. J. Schnedl, M. Krssak, E. Bernroider, M. G. Bischof, T. Lahousen, G. Pacini, and M. Roden Reduction of Hepatic Glycogen Synthesis and Breakdown in Patients with Agenesis of the Dorsal Pancreas J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4678 - 4685. [Abstract] [Full Text] [PDF]

				C. Anderwald, E. Bernroider, M. Krssak, H. Stingl, A. Brehm, M. G. Bischof, P. Nowotny, M. Roden, and W. Waldhausl Effects of Insulin Treatment in Type 2 Diabetic Patients on Intracellular Lipid Content in Liver and Skeletal Muscle Diabetes, October 1, 2002; 51(10): 3025 - 3032. [Abstract] [Full Text] [PDF]

				M. Krebs, M. Krssak, E. Bernroider, C. Anderwald, A. Brehm, M. Meyerspeer, P. Nowotny, E. Roth, W. Waldhausl, and M. Roden Mechanism of Amino Acid-Induced Skeletal Muscle Insulin Resistance in Humans Diabetes, March 1, 2002; 51(3): 599 - 605. [Abstract] [Full Text] [PDF]

				M. G. Bischof, E. Bernroider, M. Krssak, M. Krebs, H. Stingl, P. Nowotny, C. Yu, G. I. Shulman, W. Waldhausl, and M. Roden Hepatic Glycogen Metabolism in Type 1 Diabetes After Long-Term Near Normoglycemia Diabetes, January 1, 2002; 51(1): 49 - 54. [Abstract] [Full Text] [PDF]