Regulation of Glycemia and Energy Substrate Partitioning in Exercising Humans

To gain a more complete understanding of glycemic regulation and energy substrate metabolism during exercise, we examined the effects of endurance training, exercise intensity, and plasma lactate concentration on gluconeogenesis (GNG), hepatic glycogenolysis (GLY), whole body lactate turnover, and direct versus indirect lactate oxidation rates in fasted men exercising at and just below the lactate threshold (LT), where GNG precursor lactate availability is high. The lactate threshold, characterized as the onset of rapid blood lactate accumulation during incremental exercise, marks the transition between steady and non-steady state lactate turnover. We studied six untrained (UT) and six trained (T) subjects during 60-min exercise bouts at power outputs (PO) eliciting the LT. Trained subjects performed two additional exercise bouts at a PO 10% lower (LT-10%), one of which involved a lactate clamp (LC) to match blood lactate concentration ([lactate]b) to that achieved during the LT trial. Flux rates were determined by primed continuous infusion of [6,6-2H2]glucose, [3-13C]lactate, and [13C]bicarbonate tracers during 90 min of rest and 60 min of cycling. Exercise at LT corresponded to 67.6 ± 1.3 and 74.8 ± 1.7 % of peak oxygen consumption (VO2peak) in the untrained and trained subjects, respectively (P < 0.05). Relative exercise intensity was matched between the untrained group at LT and the trained group at LT-10%, and [lactate]b during exercise was matched in the LT and LT-10%+LC trials via exogenous lactate infusion. We found that increasing [lactate]b in the LT-10%+LC trial significantly increased GNG (4.4 ± 0.9 mg·kg-1·min-1) compared to its corresponding LT-10% control (1.7 ± 0.4 mg·kg-1·min-1, P < 0.05). Hepatic GLY was higher in T than UT subjects, but not significantly different across conditions. At LT, lactate rate of appearance (Ra) was nearly doubled in T than UT subjects (24.1 ± 2.7 vs. 14.6 ± 2.4 mg·kg-1·min-1, respectively, P < 0.05), but Ra was not different between UT and T when relative exercise intensities were matched at 67% VO2peak. In all trials, [lactate]b remained constant during exercise, confirming the equivalent rates of lactate appearance and disposal (Rd). At LT, metabolic clearance rate (MCR), defined as the ratio of Rd/[lactate]b, in T was 34% higher than in UT (62.5 ± 5.0 vs. 46.5 ± 7.0 ml·kg-1·min-1, respectively, P < 0.05), and a 10% reduction in PO resulted in a 46% increase in MCR at LT-10% (91.5 ± 14.9 ml·kg-1·min-1, P < 0.05), suggesting a lactate clearance limitation at LT. Total lactate oxidation rate (Rox) was higher at LT in T (22.7 ± 2.9 mg·kg-1·min-1, 75% VO2peak) compared to UT (13.4 ± 2.5 mg·kg-1·min-1, 68% VO2peak, P < 0.05). Increasing [lactate]b significantly increased lactate Rox compared to its corresponding LT-10% control (27.9 ± 3.0 vs. 15.9 ± 2.2 mg·kg-1·min-1, respectively, P < 0.05). We partitioned lactate Rox into its direct versus indirect (glucose that is gluconeogenically derived from lactate and subsequently oxidized) components. Direct and indirect lactate oxidation rates increased significantly from rest to exercise and their relative partitioning remained relatively constant in all trials, but differed between T and UT: direct oxidation comprised 75% of total lactate oxidation in UT and 90% in T suggesting the presence of training-induced adaptations. We conclude that i) endurance training increases the work capacity at the lactate threshold without a significant decrease in gluconeogenesis, ii) gluconeogenesis during exercise can be augmented by increased precursor delivery, iii) the lactate threshold represents a limitation in lactate clearance, iv) endurance training increases direct oxidation of lactate (90% in trained vs. 75% in untrained), regardless of activity level, suggesting underlying training-induced adaptations independent of exercise parameters, and v) exogenous lactate infusion during exercise spares muscle glycogen utilization.

Advisor: Brooks, George A.