Metabolic Effects of Hyperglycemia and Hyperinsulinemia on Fate of Intracellular Glucose in NIDDM

Hyperglycemia in non-insulin-dependent diabetes mellitus (NIDDM) stimulates peripheral glucose uptake, which tends to compensate for impaired insulinmediated glucose uptake. The metabolic fate of glucose and suppression of fat oxidation may differ, however, when glucose uptake is stimulated primarily by insulin or hyperglycemia. To address this issue, three hyperinsulinemic glucose-clamp studies were performed in combination with indirect calorimetry in seven nonobese subjects with NIDDM. In the first two experiments, when glucose uptake was matched at ∼8 mg · kg−1 fat-free mass (FFM) · min1 with primarily hyperinsulinemia (1350 ± 445 pM) or hyperglycemia (20.8 ± 1.8 mM), identical rates of glucose oxidation (3.21 ± 0.29 and 3.10 ± 0.23 mg · kg−1 FFM · min−1, NS) and nonoxidative glucose metabolism (5.19 ± 0.75 and 5.46 ± 0.61 mg · kg−1 FFM · min−1, NS) were achieved. When glucose uptake was increased further to 11.11 ± 0.36 mg · kg−1 FFM · min−1 with less insulin (625 ± 70 pM) and hyperglycemia, glucose oxidation (3.85 ± 0.26 mg · kg−1 FFM · min−1) and nonoxidative glucose metabolism (7.26 ± 0.51 mg · kg−1 FFM min−1) rose significantly (both P < 0.05 from matched studies at lower rates of glucose uptake). During all glucose-clamp studies, free fatty acids were comparably suppressed by 40–46% (all P < 0.005 vs. basal values), whereas fat oxidation was suppressed by 70–80% (all P < 0.005 vs. basal values). A strong negative correlation was observed between rates of glucose and fat oxidation (r = −0.88, P < 0.001) when all studies were combined. These results demonstrate that, when hyperglycemia compensates for impaired insulin-mediated glucose uptake in NIDDM, the ultimate intracellular movement of glucose into oxidative and nonoxidative pathways remains unchanged and the rate of glucose uptake rather than the level of serum insulin determines the disposition of infused glucose. The development of hyperglycemia in NIDDM appears to function as a regulatory mechanism compensating not only for impaired glucose uptake but also for the pathways of intracellular glucose metabolism.