CONTRIBUTION OF OBESITY TO INSULIN-RESISTANCE IN NONINSULIN-DEPENDENT DIABETES-MELLITUS

Inasmuch as previous studies have obtained conflicting results on the contribution of obesity to insulin resistance in noninsulin-dependent diabetes mellitus (NIDDM), we studied 10 nonobese and 10 obese NIDDM patients with the isoglycemic- (similar to 10 mmol/L)-hyperinsulinemic clamp (two insulin infusions of 4 and 40 mU/m(-2) min(-1)), combined with [3-H-3]glucose infusion and indirect calorimetry. As compared with nonobese patients, obese NIDDM patients had higher baseline peripheral and estimated portal plasma insulin concentrations (113 +/- 18 vs. 46 +/- 3 pmol/L and 288 +/- 53 vs. 98 +/- 6 pmol/L, respectively; P < 0.05) and less suppressed endogenous insulin production during clamp. Hepatic glucose production was greater in obese than in nonobese patients (basal, 16 +/- 1.1 vs. 12 +/- 0.5 mu mol/kg(-1) fat-free mass (FFM) min(-1); clamp, 5.7 +/- 0.5 vs. 2.8 +/- 0.2 mu mol/kg(-1) FFM min(-1), P < 0.05). Glucose utilization increased to a lesser extent in obese than in nonobese patients (49 +/- 5 vs. 73 +/- 7 mu mol/kg(-1) FFM min(-1), P < 0.05) during clamp because of a lower increase in nonoxidative glucose metabolism (30 +/- 5 vs. 50 +/- 7 mu mol/kg(-1) FFM min(-1), P < 0.05). Plasma free fatty acid concentrations and rates of lipid oxidation were greater in obese (P < 0.05) patients and correlated with hepatic glucose production (r = 0.79 and 0.50, P < 0.05). In conclusion, obesity exaggerates hepatic as well as extra-hepatic insulin resistance in NIDDM. The impaired inhibition of pancreatic beta-cell function by exogenous insulin contributes to exaggerated hyperinsulinemia in obese NIDDM.