Regulation of Glucose Uptake and Metabolism by Working Muscle: An In Vivo Analysis

To assess the mechanisms whereby muscular work stimulates glucose uptake and metabolism in vivo, dogs were studied during rest (–40–0 min), moderate exercise (0–90 min), and exercise recovery (90–180 min) with plasma glucose clamped at 5.0, 6.7, 8.3, and 10.0 mM (n = 5 at 5.0 mM and n = 4 at all other levels) using a variable glucose infusion. Basal insulin was maintained with somatostatin and insulin replacement. Whole-body glucose uptake, limb glucose uptake, and oxidative and nonoxidative glucose plus lactate metabolism, were assessed with tracers ([3H]glucose and [14C]glucose) and arteriovenous differences. The combined effects of glucose and exercise on the increment above resting values for limb glucose uptake, arteriovenous glucose difference, LGO, LGNO, and rate of glucose disappearance were synergistic (∼ 112, 90, 125, 76, and 90% > the additive values, respectively). Neither exercise nor recovery affected the Km for limb glucose uptake (4.7 ± 1.1, 4.8 ± 0.4, and 5.2 ± 0.3 mM during rest, exercise, and recovery, respectively), but both conditions increased the Vmax (44 ± 16, 217 ± 30, and 118 ± 14 mumol/min during rest, exercise, and recovery, respectively). Similarly, the Km for arteriovenous glucose differences were unaffected by exercise recovery (4.9 ± 0.6, 5.0 ± 0.4, and 5.3 ± 0.3 mM during rest, exercise, and recovery, respectively), but the maximum rose (272 ± 50, 650 ± 78, and 822 ± 111 microM during rest, exercise, and recovery, respectively). The LGO was unchanged by glycemia at rest (15 ± 4 mumol/min at 10.0 mM). The Km for LGO during exercise was 5.1 ± 0.3 mM, and the Vmax was 163 ± 15. The capacity for LGO returned to basal during recovery. LGNO increased gradually with increasing glycemia during rest, exercise, and recovery and did not approach saturation (38 ± 13, 105 ± 36, and 132 ± 45 mumol/min during rest, exercise, and recovery, respectively, at 10.0 mM). In general, the LGNO was elevated at every glucose level during exercise (∼ twofold) and recovery (∼ threefold) compared with rest. Arterial free fatty acid and glycerol levels decreased with increasing glycemia within all periods. Free fatty acids were suppressed by a greater amount during exercise compared with rest and recovery. This study shows that 1) the combined effects of exercise and increased glucose level act synergistically on glucose uptake and metabolism; 2) exercise increases the V_max for limb glucose uptake and arteriovenous glucose difference without altering the K_m for these variables; 3) the capacity for LGNO predominates at rest, whereas the capacity for LGO predominates during exercise; 4) during recovery the capacity for LGO returned to basal, whereas that for LGNO remained elevated; and 5) glucose-induced suppression of free fatty acid levels was greatest during exercise. In conclusion, an increase in circulating glucose within the physiological range, which has only minor effects at rest, profoundly increases muscle glucose metabolism and decreases free fatty acid availability during exercise.