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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.

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