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The present study sought to determine whether elevated plasma free fatty acids (FFAs) alter the splanchnic and muscle glucose metabolism in women. To do so, FFAs were increased in seven women by an 8-h Intralipid/heparin (IL/hep) infusion, and the results were compared with those observed in nine women who were infused with glycerol alone. Glucose was clamped at ∼8.3 mmol/l and insulin was increased to ∼300 pmol/l to stimulate both muscle and hepatic glucose uptake. Insulin secretion was inhibited with somatostatin. Leg and splanchnic glucose metabolism were assessed using a combined catheter and tracer dilution approach. The glucose infusion rates required to maintain target plasma glucose concentrations were lower (P < 0.01) during IL/hep than glycerol infusion (30.8 ± 2.6 vs. 650 ± 7.9 µmol · kg[sup -1] · min[sup -1]). Whole body glucose disappearance (37.0 ± 2.2 vs. 70.9 ± 8.7 µmol · kg[sup -1] · min[sup -1]; P < 0.001) and leg glucose uptake (24.3 ± 4.2 vs. 59.6 ± 10.0 µmol · kg fat-free mass of the leg[sup -1] · min[sup -1]; P < 0.02) were also lower, whereas splanchnic glucose production (8.2 ± 0.8 vs. 4.3 ± 0.7 µmol · kg[sup -1] · min[sup -1]; P < 0.01) was higher during IL/hep than glycerol infusion. We conclude that in the presence of combined hyperinsulinemia and hyperglycemia, elevated FFAs impair glucose metabolism in women by inhibiting wholebody glucose disposal, muscle glucose uptake, and suppression of splanchnic glucose production. [ABSTRACT FROM AUTHOR]