Dose-response characteristics of impaired glucose oxidation in non-insulin-dependent diabetes mellitus

To determine the dose-response characteristics of impaired glucose oxidation in non-insulin-dependent diabetes mellitus (NIDDM), indirect calorimetry was performed on eight matched control and NIDDM subjects during the basal state and during three glucose clamps at insulin infusion rates of 150, 300, and 1,500 pmol.m-2.min-1. Hyperglycemia was used to achieve matched rates of glucose uptake at each insulin infusion. Glucose uptake in the basal state was greater in NIDDM [3.75 +/- 0.23 vs. 2.50 +/- 0.10 mg.kg fat-free mass (FFM)-1.min-1, P less than 0.005] but was similar at approximately 8, 12, and 26 mg.kg FFM-1.min-1 at each insulin infusion. Basal protein oxidation, fat oxidation, and plasma free fatty acids were similar and equally sensitive to suppression by insulin in both groups. Glucose oxidation was reduced 20-26%, and circulating lactate increased 50-90% at physiological but not at pharmacological insulin concentrations in NIDDM. The dose-response relationship between serum insulin and glucose oxidation was right shifted in NIDDM with half-maximal activation at 368 +/- 91 vs. 179 +/- 27 pM in controls (P less than 0.05). In conclusion, glucose oxidation is reduced at physiological insulin concentrations in NIDDM and cannot be explained by concomitant obesity, increased fat oxidation, or reduced glucose uptake but results from impaired sensitivity to stimulation by insulin, possibly at pyruvate dehydrogenase.