Kinetics of In Vivo Muscle Insulin-Mediated Glucose Uptake in Human Obesity

Abstract

The kinetics of in vivo insulin-mediated glucose uptake in human obesity have not been previously studied. To examine this, we used the glucose-clamp technique to measure whole-body and leg muscle glucose uptake in seven lean and six obese men during hyperinsulinemia (∼2000 pM) at four glucose levels (∼4.5, ∼8.3, ∼13.5, and ∼23.5 mM). To measure leg glucose uptake, the femoral artery and vein were catheterized, and blood flow was measured by thermodilution (leg glucose uptake = arteriovenous glucose difference × blood flow). With this approach, we found that rates of whole-body and leg glucose uptake were significantly lower in obese than in lean subjects at each glucose plateau. Leg blood flow rates increased from 4.3 ± 0.4 to 6.5 ± 0.8 dl/min over the range of glucose in lean subjects (P < 0.05) but remained unchanged in obese subjects. The apparent maximal capacity (Vmax), based on whole-body and leg glucose uptake, was reduced in obese compared with lean subjects, but the apparent Km was similar in the lean and obese subjects (6-9 mM, NS). To assess the affinity of muscle for glucose extraction independent of changes in muscle plasma flow, we determined the mean half-maximal effective glucose concentration (EG50) and found it was similar in the lean and obese subjects (6.0 ± 0.3 vs. 6.0 ± 0.8 mM, NS). We conclude that 1) the kinetics of in vivo insulin-mediated glucose uptake in skeletal muscle in human obesity are characterized by reduced Vmax but normal Km; 2) the EG50 for insulin-mediated glucose extraction in skeletal muscle was 6 mM in both lean and obese subjects, consistent with a Km characteristic of the glucose-transport system; 3) obese subjects were unable to generate increases in blood flow in response to hyperglycemia under hyperinsulinemic conditions, and this contributed significantly to lower rates of leg and whole-body glucose uptake.