CONTRIBUTION OF OBESITY TO DEFECTS OF INTRACELLULAR GLUCOSE-METABOLISM IN NIDDM

OBJECTIVE- To examine the contribution of obesity to insulin resistance and abnormalities of intracellular glucose and fat metabolism in NIDDM. RESEARCH DESIGN AND METHODS- Glucose turnover measurements and indirect calorimetry were performed in 10 obese non-insulin-dependent diabetes mellitus (NIDDM) and 10 lean NIDDM subjects (body mass index 35.3 +/- 1.0 vs. 24.1 +/- 0.5 kg/m(2), P less than or equal to 0.001) in the basal state and during hyperinsulinemic (720 pmol . m(-2). min(-1)) euglycemic (5.0-5.5 mmol/l) clamps. RESULTS- Obese and lean NIDDM subjects demonstrated similar basal rates of glucose uptake (GU) (1.15 +/- 0.08 vs. 1.26 +/- 0.08 mmol/min, NS) as well as oxidative (0.49 +/- 0.07 vs. 0.53 +/- 0.05 mmol/min, NS) and nonoxidative (0.67 +/- 0.10 vs. 0.73 +/- 0.12 mmol/min, NS) glucose metabolism. During hyperinsulinemic glucose clamp studies, rates of GU were lower in obese NIDDM subjects (34.1 +/- 2.3 vs. 55.2 +/- 3.8 mu mol . kg fat-free mass [FFM](-1). min(-1), P less than or equal to 0.001) as were rates of oxidative (14.1 +/- 1.3 vs. 22.1 +/- 2.1 mu mol . kg FFM(-1). min(-1), P less than or equal to 0.005) and nonoxidative (20.0 +/- 2.3 vs. 33.1 +/- 3.6 mu mol . kg FFM(-1). min(-1), P less than or equal to 0.01) glucose metabolism. Although absolute rates of insulin-stimulated GU were decreased in the obese group, the relative distribution into glucose oxidation (G(ox)) and nonoxidative glucose metabolism (N-ox) was comparable in both groups (G(ox) 42% in obese and 41% in lean subjects; N-ox 58% in obese and 59% in lean subjects). The NIDDM groups had similar basal free fatty acid levels that were suppressed equally during hyperinsulinemic clamps. However, basal fat oxidation (F-ox) was greater in the obese NIDDM group (103 +/- 11 vs. 73 +/- 8 mu mol/min, P less than or equal to 0.05) and was less suppressed to insulin (74 +/- 13 vs. 16 +/- 3 mu mol/ min, P less than or equal to 0.001). CONCLUSIONS- These results indicate that when obesity is present in NIDDM subjects with this degree of hyperglycemia, insulin-stimulated GU is lower by 35-40%. Reduced GU in obese NIDDM subjects leads to decreased intracellular substrate availability and lower rates of oxidative and nonoxidative glucose metabolism. Insulin suppression of F-ox is also impaired when obesity is present and may contribute to decreased insulin-mediated GU in NIDDM. We conclude that obesity increases insulin resistance in NIDDM primarily by effects on GU rather than the intracellular pathways of glucose metabolism.