Effect of Hyperinsulinemia and Hyperglycemia on Intracellular Glucose and Fat Metabolism in Healthy Subjects

Hyperinsulinemia and hyperglycemia per se both stimulate glucose uptake and the disposal of glucose by oxidative (Gox) and nonoxidative (Nox) metabolism. However, the intracellular metabolic fate of glucose may not be the same when glucose uptake is stimulated predominantly by either of these mechanisms due to different effects on fat oxidation (Fox). To address this issue, 11 healthy subjects each had four glucose-clamp studies performed in combination with indirect calorimetry to compare Gox, Nox, and Fox at two different rates of glucose uptake (∼7 and 10 mg · kg−1 fat-free mass [FFM] · min−1) matched at each level by either hyperglycemia or hyperinsulinemia. When glucose uptake was matched at the lower rate (7 mg · kg−1 FFM · min−1), there was less suppression of both FFA (33 vs. 43%, P < 0.05) and Fox (73 vs. 90%, P < 0.05) and less stimulation of incremental (above basal) Gox (1.95 vs. 2.49 mg · kg−1 FFM · min−1 P < 0.025) at low insulin (72 pM) and hyperglycemia (21.8 mM) compared with high insulin (280 pM) and euglycemia (5.1 mM). Matching glucose uptake at the higher rates (10 mg · kg−1 FFM · min−1) required >300 pM of insulin (309 and 632 pM) in both studies and resulted in maximal suppression of FFA (49 vs. 46%, NS) and Fox (both >90%, NS) and similar incremental Gox (2.89 vs. 2.73 mg · kg−1 FFM · min−1, NS) whether at hyperglycemia (15.7 mM) or euglycemia (5.2 mM). Therefore, both hyperinsulinemia and hyperglycemia stimulate glucose uptake and increase intracellular glucose availability, but insulin also regulates Gox by suppression of FFA and Fox. However, when FFA and Fox are maximally suppressed, the rate of glucose uptake, rather than the prevailing insulin level, determines the distribution of intracellular glucose metabolism.