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-(~10 mmol/L)-hyperinsulinemic clamp (two insulin infusions of 4 and 40 mU/m^-2 min^-1), combined with [3-³H] 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 ± 05 μmol/kg^-1 fat-free mass (FFM) min^-1; clamp, 5.7 ± 0.5 vs. 2.8 ± 0.2 μmol/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 μmol/kg^-1 FFM min^-1, P < 0.05) during clamp because of a lower increase in nonoxidative glucose metabolism (30 ± 5 vs. 50 ± 7 μmol/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 β-cell function by exogenous insulin contributes to exaggerated hyperinsulinemia in obese NIDDM.