1. The purpose of the present study was to maintain physiological plasma non-esterified fatty acid levels and to (i) examine their effect on skeletal muscle insulin-stimulated glucose uptake and metabolite exchange using the forearm technique, and (ii) evaluate their effect on whole-body glucose uptake and fuel oxidation.

2. Intralipid (10%) and heparin (Lipid) or saline (Control) was administered to eight healthy male subjects on separate occasions for 210 min. Insulin, glucagon and somatostatin were administered from 60 to 210 min in each study and euglycaemia was maintained.

3. Plasma non-esterified fatty acid levels plateaued at 420 ±50 μmol/l with the Lipid infusion but were completely suppressed during the Control clamp. Forearm non-esterified fatty acid uptake increased with the Lipid infusion (+ 50±10 nmol min−1 100 ml−1 of forearm) and was accompanied by a significant decrease in forearm glucose uptake (+ 3.23 ± 0.25 versus + 3.65 ± 0.35 μmol min−1 100 ml−1 of forearm, Lipid and Control, respectively; P < 0.05) and alanine release (–84±12 versus −113 ± 15 nmol min−1 100 ml−1 of forearm, Lipid and Control, respectively; P < 0.05).

4. Whole-body glucose uptake showed a comparable decrease with the Lipid infusion (6.36 ±0.81 versus 6.85±0.66 mg min−1 kg−1; P < 0.05) and was accompanied by an increase in lipid oxidation (0.33 ±0.08 versus 0.16 ±0.05 mg min−1 kg−1; P < 0.02) and a decrease in glucose oxidation (2.93 ±0.23 versus 3.30±0.20 mg min−1 kg−1; P < 0.05).

5. We conclude that the maintenance of physiological plasma non-esterified fatty acid levels is associated with a decrease in forearm and whole-body insulin-stimulated glucose uptake. The changes in substrate oxidation and forearm alanine exchange provide support for the operation of the glucose—fatty acid cycle.

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