NEFAs characteristically are elevated in obese NIDDM patients in both the basal state and after insulin. This elevation might aggravate glycemic control both by decreasing peripheral glucose disposal (glucose-fatty acid cycle), and by increasing HGO. Thus, lowering plasma NEFA levels might improve carbohydrate metabolism. We therefore measured HGO and fuel use (by indirect calorimetry) both in the basal state and during the last 30 min of a hyperinsulinemic clamp (0.025U · kg⁻¹ · h⁻¹) in 8 obese NIDDM patients (BMI 34.8 ±1.0 kg/m²) after complete overnight suppression of plasma NEFA levels with acipimox, a new nicotinic acid analogue. After acipimox, mean basal plasma NEFA and glycerol levels were lower than control values (0.11 ± 0.02 vs. 0.65 ±0.04 mM, P < 0.001; and 16 ± 3 vs. 68 ± 7 μM, P = 0.004, respectively) and were accompanied by a fall in lipid oxidation (acipimox vs. placebo: 16.1 ±1.2 vs. 38.8 ± 2.4 mg · m⁻² · min⁻¹; P < 0.001) and a rise in glucose oxidation (91.1 ± 6.2 vs. 54.1 ± 9.0 mg · m⁻² · min⁻¹; P = 0.002). Basal HGO and fasting plasma glucose levels were lower (94.1 ± 9.2 vs. 118.5 ± 9.5 mg · m⁻² · min⁻¹ P = 0.01; and 8.3 ± 1.2 vs. 9.8 ± 1.2 mM; P < 0.001), respectively. Serum insulin levels were similar during the clamps (44.2 ± 4.9 vs. 48.2 ± 5.7 μU/L; NS), but despite this, HGO was suppressed more after acipimox (18.2 ± 7.6 vs. 49.7 ± 12.9 mg · m⁻² · min⁻¹; P < 0.01), and the metabolic clearance rate for glucose was higher (101.98 ± 19.34 vs. 75.43 ± 9.94 ml · m⁻² · min⁻¹; P < 0.05). In conclusion, prolonged overnight suppression of lipolysis and lipid oxidation in obese NIDDM lowers fasting blood glucose and HGO and increases peripheral and hepatic sensitivity to insulin in obese NIDDM patients.