Free fatty acids inhibit the glucose-stimulated increase of intramuscular glucose-6-phosphate concentration in humans

To test Randle's hypothesis we examined whether free fatty acids (FFAs) aff ect glucose-stimulated glucose transport/phosphorylation and allosteric med iators of muscle glucose metabolism under conditions of fasting peripheral insulinemia. Seven healthy men were studied during somatostatin-glucose-ins ulin clamp tests [plasma insulin, 50 pmol/L; plasma glucose, 5 mmol/L (0-18 0 min), 10 mmol/L (180-300 min)l in the presence of low (0.05 mmol/L) and i ncreased (2.6 mmol/L) plasma FFA concentrations. P-31 and H-1 nuclear magne tic resonance spectroscopy was used to determine intracellular concentratio ns of glucose-6-phosphate (G6P), inorganic phosphate, phosphocreatine, ADP, pH, and intramyocellular lipids. Rates of glucose turnover were measured u sing D-[6,6-H-2(2)]glucose. Plasma FFA ele-vation reduced rates of glucose uptake at the end of the euglycemic period (Rd 150-180 min: 8.6 +/- 0.5 vs. 12.6 +/- 1.6 mu mol/kg.min, P < 0.05) and during hyperglycemia (Rd 270-300 min: 9.9 +/- 0.6 vs. 22.3 +/- 1.7 mu mol/kg.min, P < 0.01). Similarly, int ramuscular G6P was lower at the end of both euglycemic (Delta G6P(167-180 m in): -22 +/- 7 us. +24 +/- 7 mu mol/L, P < 0.05) and hyperglycemic periods (Delta G6P(287-300 min): -7 +/- 9 us. +28 +/- 7 mu mol/L, P < 0.05). Change s in intracellular inorganic phosphate exhibited a similar pattern, whereas FFA did not affect phosphocreatine, ADP, pH, and intramyocellular lipid co ntents. In conclusion, the lack of an increase in muscular G6P along with r eduction of whole body glucose clearance indicates that FFA might directly inhibit glucose transport/phosphorylation in skeletal muscle.