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/m2, 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 micromole.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 micromole.kg FFM-1.min-1, P micromole 0.005) and nonoxidative (20.0 +/- 2.3 vs. 33.1 +/- 3.6 micromole.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 micromole/min, P less than or equal to 0.05) and was less suppressed to insulin (74 +/- 13 vs. 16 +/- 3 micromole/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.