OBJECTIVE: This study intended to investigate disturbances in beta-adrenergically-mediated substrate utilization and thermogenesis in obese subjects with mild non insulin-dependent diabetes mellitus (NIDDM). DESIGN: Following a baseline period of 30 min, the beta-agonist isoproterenol (ISO) was administered in increasing doses of 6, 12, and 24 ng/kgFFM x min, each dose for 30 min. SUBJECTS: Nine healthy lean males (CON, 50.6+/-2.4 y, % body fat: 16.0+/-1.8) and 10 obese subjects with NIDDM (51.8+/-2.4 y, % body fat 34.1+/-1.9). RESULTS: Basal non esterified fatty acid concentrations (NEFA) and basal fat oxidation (absolute or expressed per unit fat free mass, FFM) were significantly higher in NIDDM as compared to CON, whereas basal carbohydrate (CHO) oxidation was significantly lower. The ISO-induced increase in NEFA-concentrations was blunted in NIDDM (delta at 24 ng/kgFFM x min: CON: 717+/-59 micromol/l vs NIDDM: 358+/-97 micromol/l, P< 0.01). The non-protein respiratory exchange ratio (RER) did not change in NIDDM and significantly decreased in CON during ISO-infusion (P < 0.05), reflecting the tendency towards a blunted increase in fat oxidation in NIDDM (delta fat ox at 24 ng; CON: 0.025+/-0.005 g/min vs NIDDM 0.016+/-0.007 g/min). The ISO-induced thermogenic response was comparable in NIDDM and CON (at 24 ng %increase above baseline: CON: 16.8+/-2.2% vs NIDDM: 14.7+/-0.9%). At all time points, there were no significant differences in circulating ISO and noradrenaline concentrations. Basal adrenaline (A) concentrations and A concentrations during ISO-infusion were significantly lower in NIDDM (basal A; CON: 64+/-15 pg/ml vs NIDDM: 25+/-2 pg/ml, P < 0.001). CONCLUSION: There appear to be deviations in beta-adrenoceptor mediated fat utilization and adrenal medulla function in obesity-associated NIDDM. The impairments in sympathetically mediated fat utilization have previously been observed in 'simple' obese subjects, indicating that these disturbances are confined to the obese state per se.