Endurance training improves oxygen uptake/demand mismatch, metabolic flexibility and recovery in patients with sickle cell disease.

Patients with sickle cell disease (SCD) display lower slope coefficients of the oxygen uptake (V̇O2) versus work rate (W) relationship (delineating an O2 uptake/demand mismatch) and a poor metabolic flexibility. Because endurance training improves the microvascular network and increases the activity of oxidative enzymes, including one involved in lipid oxidation, endurance training might improve the slope coefficient of the V̇O2 versus W curve and the metabolic flexibility of SCD patients. Endurance training may also contribute to improve patients' post-exercise cardiopulmonary and metabolic recovery. Fifteen patients with SCD performed a submaximal incremental test on a cycle ergometer before (SIT1) and after (SIT2) 8 weeks of endurance training. Minute ventilation (V̇ E), ventilation rate, heart rate, V̇O2, carbon dioxide production (V̇CO2), respiratory exchange ratio, carbohydrate/lipid utilization and partitioning (including %Lipidox) and blood lactate concentration were measured during and after SIT1 and SIT2. At baseline, the slope coefficient of the V̇O2 versus W curve positively correlated with total hemoglobin, mean corpuscular hemoglobin and percentage of HbF. After training, the slope coefficient of the V̇O2 versus W curve was significantly higher and the increase in blood lactate concentration was delayed. If patients' energy metabolism apparently relied largely on carbohydrate sources during SIT1, %Lipidox tended to increase at low exercise intensities during SIT2, supporting a training-induced improvement of metabolic flexibility in patients with SCD. Post-exercise recovery of ventilation rate, V̇ E/V̇CO2, heart rate and blood lactate concentration was faster after training. We concluded that exercise training in patients with SCD: (i) ameliorated the oxygen uptake/ demand mismatch, (ii) blunted the metabolic inflexibility, and (iii) improved post-exercise cardiopulmonary and metabolic responses.

Concepts of Lactate Metabolic Clearance Rate and Lactate Clamp for Metabolic Inquiry: A Mini-Review.

Lactate is known to play a central role in the link between glycolytic and mitochondrial oxidative metabolism, as well as to serve as a primary gluconeogenic precursor. Blood lactate concentration is sensitive to the metabolic state of tissues and organs as lactate rates of appearance and disposal/disappearance in the circulation rise and fall in response to physical exercise and other metabolic disturbances. The highest lactate flux rates have been measured during moderate intensity exercise in endurance-trained individuals who exhibit muscular and metabolic adaptations lending to superior oxidative capacity. In contrast, a diminished ability to utilize lactate is associated with poor metabolic fitness. Given these widespread implications in exercise performance and health, we discuss the concept of lactate metabolic clearance rate, which increases at the onset of exercise and, unlike flux rates, reaches a peak just below the power output associated with the maximal lactate steady state. The metabolic clearance rate is determined by both disposal rate and blood concentration, two parameters that are mutually interdependent and thus difficult to parse during steady state exercise studies. We review the evolution of the in vivo lactate clamp methodology to control blood lactate concentration and discuss its application in the investigation of whole-body lactate disposal capacities. In conclusion, we assert that the lactate clamp is a useful research methodology for examining lactate flux, in particular the factors that drive metabolic clearance rate.

Delayed Rebound of Glycemia During Recovery Following Short-Duration High-Intensity Exercise: Are There Lactate and Glucose Metabolism Interactions?

Lactate constitutes the primary gluconeogenic precursor in healthy humans at rest and during low-intensity exercise. Data on the interactions between lactate and glucose metabolisms during recovery after short-duration high-intensity exercise are sparse. The aim of the present study was to describe blood glucose ([glucose]b) and lactate ([lactate]b) concentration curves during recovery following short-duration high-intensity exercise. Fifteen healthy Cameroonian subjects took part in the study and performed successively (i) an incremental exercise to exhaustion to determine maximal work rate (Pmax) and (ii) a 2-min 110% Pmax exercise after which blood lactate and glucose concentrations were measured during the 80-min passive recovery. In response to the 2-min 110% Pmax exercise, [glucose]b remained stable (from 4.93 ± 1.13 to 4.65 ± 0.74 mmol.L-1, NS) while [lactate]b increased (from 1.35 ± 0.36 to 7.87 ± 1.66 mmol.L-1, p < 0.0001). During recovery, blood lactate concentrations displayed the classic biphasic curve while blood glucose concentrations displayed a singular shape including a delayed and transitory rebound of glycemia. This rebound began at 27.7 ± 6.2 min and peaked at 6.78 ± 0.53 mmol.L-1 at 56.3 ± 9.7 min into recovery. The area under the curve (AUC) of [lactate]b during the rebound of glycemia was positively correlated with the peak value of glycemia and the AUC of [glucose]b during the rebound. In conclusion, the delayed rebound of glycemia observed in the present study was associated with lactate availability during this period.

Skeletal Muscle Hyperemia: A Potential Bridge Between Post-exercise Hypotension and Glucose Regulation.

For both healthy individuals and patients with type 2 diabetes (T2D), the hemodynamic response to regular physical activity is important for regulating blood glucose, protecting vascular function, and reducing the risk of cardiovascular disease. In addition to these benefits of regular physical activity, evidence suggests even a single bout of dynamic exercise promotes increased insulin-mediated glucose uptake and insulin sensitivity during the acute recovery period. Importantly, post-exercise hypotension (PEH), which is defined as a sustained reduction in arterial pressure following a single bout of exercise, appears to be blunted in those with T2D compared to their non-diabetic counterparts. In this short review, we describe research that suggests the sustained post-exercise vasodilation often observed in PEH may sub-serve glycemic regulation following exercise in both healthy individuals and those with T2D. Furthermore, we discuss the interplay of enhanced perfusion, both macrovascular and microvascular, and glucose flux following exercise. Finally, we propose future research directions to enhance our understanding of the relationship between post-exercise hemodynamics and glucose regulation in healthy individuals and in those with T2D.

Direct and indirect lactate oxidation in trained and untrained men.

Lactate has been shown to be an important oxidative fuel. We aimed to quantify the total lactate oxidation rate (Rox) and its direct vs. indirect (glucose that is gluconeogenically derived from lactate and subsequently oxidized) components (mg·kg(-1)·min(-1)) during rest and exercise in humans. We also investigated the effects of endurance training, exercise intensity, and blood lactate concentration ([lactate]b) on direct and indirect lactate oxidation. Six untrained (UT) and six trained (T) men completed 60 min of constant load exercise at power outputs corresponding to their lactate threshold (LT). T subjects completed two additional 60-min sessions of constant load exercise at 10% below the LT workload (LT-10%), one of which included a lactate clamp (LC; LT-10%+LC). Rox was higher at LT in T [22.7 ± 2.9, 75% peak oxygen consumption (Vo2peak)] compared with UT (13.4 ± 2.5, 68% Vo2peak, P < 0.05). Increasing [lactate]b (LT-10%+LC, 67% Vo2peak) significantly increased lactate Rox (27.9 ± 3.0) compared with its corresponding LT-10% control (15.9 ± 2.2, P < 0.05). Direct and indirect Rox increased significantly from rest to exercise, and their relative partitioning remained 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. Partitioning of total carbohydrate (CHO) use showed that subjects derived one-third of CHO energy from blood lactate, and exogenous lactate infusion increased lactate oxidation significantly, causing a glycogen-sparing effect in exercising muscle.

Lactate kinetics at the lactate threshold in trained and untrained men.

To understand the meaning of the lactate threshold (LT) and to test the hypothesis that endurance training augments lactate kinetics [i.e., rates of appearance and disposal (Ra and Rd, respectively, mg·kg(-1)·min(-1)) and metabolic clearance rate (MCR, ml·kg(-1)·min(-1))], 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. At LT, lactate Ra was higher in T (24.1 ± 2.7) than in UT (14.6 ± 2.4; P < 0.05) subjects, but Ra was not different between UT and T when relative exercise intensities were matched (UT-LT vs. T-LT-10%, 67% Vo2max). At LT, MCR in T (62.5 ± 5.0) subjects was 34% higher than in UT (46.5 ± 7.0; P < 0.05), and a reduction in PO resulted in a significant increase in MCR by 46% (LT-10%, 91.5 ± 14.9, P < 0.05). At matched relative exercise intensities (67% Vo2max), MCR in T subjects was 97% higher than in UT (P < 0.05). During the LC trial, MCR in T subjects was 64% higher than in UT (P < 0.05), in whom %Vo2max and [lactate]b were similar. We conclude that 1) lactate MCR reaches an apex below the LT, 2) LT corresponds to a limitation in MCR, and 3) endurance training augments capacities for lactate production, disposal and clearance.

Gluconeogenesis and hepatic glycogenolysis during exercise at the lactate threshold.

Because the maintenance of glycemia is essential during prolonged exercise, we examined the effects of endurance training, exercise intensity, and plasma lactate concentration ([lactate]) on gluconeogenesis (GNG) and hepatic glycogenolysis (GLY) in fasted men exercising at, and just below, the lactate threshold (LT), where GNG precursor lactate availability is high. Twelve healthy men (6 untrained, 6 trained) completed 60 min of constant-load exercise at power outputs corresponding to their individual LT. Trained subjects completed two additional 60-min sessions of constant-load exercise: one at 10% below the LT workload (LT-10%), and the other with a lactate clamp (LT-10%+LC) to match the [lactate] of the LT trial. Flux rates were determined by primed continuous infusion of [6,6-(2)H(2)]glucose, [3-(13)C]lactate, and [(13)C]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% peak O(2) consumption 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] during exercise was matched in the LT and LT-10%+LC trials via exogenous lactate infusion. Glucose kinetics (rate of appearance, rate of disposal, and metabolic clearance rate) were augmented with the lactate clamp. GNG was decreased in the trained subjects exercising at LT and LT-10% compared with the untrained subjects, but increasing [lactate] in the LT-10%+LC trial significantly increased GNG (4.4 ± 0.9 mg·kg(-1)·min(-1)) compared with its corresponding control (1.7 ± 0.4 mg·kg(-1)·min(-1), P < 0.05). Hepatic GLY was higher in the trained than untrained subjects, but not significantly different across conditions. We conclude that GNG plays an essential role in maintaining total glucose production during exercise in fasted men, regardless of training state. However, endurance training increases the ability to achieve a higher relative exercise intensity and absolute power output at the LT without a significant decrease in GNG. Furthermore, raising systemic precursor substrate availability increases GNG during exercise, but not at rest.

Transpulmonary lactate shuttle.

The shuttling of intermediary metabolites such as lactate through the vasculature contributes to the dynamic energy and biosynthetic needs of tissues. Tracer kinetic studies offer a powerful tool to measure the metabolism of substrates like lactate that are simultaneously taken up from and released into the circulation by organs, but in each circulatory passage, the entire cardiac output traverses the pulmonary parenchyma. To determine whether transpulmonary lactate shuttling affects whole-body lactate kinetics in vivo, we examined the effects of a lactate load (via lactate clamp, LC) and epinephrine (Epi) stimulation on transpulmonary lactate kinetics in an anesthetized rat model using a primed-continuous infusion of [U-(13)C]lactate. Under all conditions studied, control 1.2 (SD 0.7) (Con), LC 1.9 (SD 2.5), and Epi 1.9 (SD 3.5) mg/min net transpulmonary lactate uptake occurred. Compared with Con, a lactate load via LC significantly increased mixed central venous ([v]) [1.9 mM (SD 0.5) vs. 4.7 (SD 0.4)] and arterial ([a]) [1.6 mM (SD 0.4) vs. 4.1 (SD 0.6)] lactate concentrations (P < 0.05). Transpulmonary lactate gradient ([v] - [a]) was highest during the lactate clamp condition [0.6 mM (SD 0.7)] and lowest during Epi [0.2 mM (SD 0.5)] stimulation (P < 0.05). Tracer measured lactate fractional extractions were similar for control, 16.6% (SD 15.3), and lactate clamp, 8.2% (SD 15.3) conditions, but negative during Epi stimulation, -25.3% (SD 45.5) when there occurred a transpulmonary production, the conversion of mixed central venous pyruvate to arterial lactate. Further, isotopic equilibration between L and P occurred following tracer lactate infusion, but depending on compartment (v or a) and physiological stimulus, [L]/[P] concentration and isotopic enrichment ratios ranged widely. We conclude that pulmonary arterial-vein concentration difference measurements across the lungs provide an incomplete, and perhaps misleading picture of parenchymal lactate metabolism, especially during epinephrine stimulation.

Histamine-receptor blockade reduces blood flow but not muscle glucose uptake during postexercise recovery in humans.

Skeletal muscle vasodilatation persists following a single bout of exercise and can potentially influence glucose uptake by recovering muscle. To investigate whether blood flow is a rate-limiting component in postexercise muscle glucose uptake, we tested the hypothesis that oral ingestion of H(1)- and H(2)-receptor antagonists, known to attenuate the sustained postexercise vasodilatation, would reduce leg glucose uptake after a bout of cycling. Healthy, recreationally active subjects (n = 8) exercised for 1 h at 60% of peak oxygen consumption on each of two days, with (blockade) and without (control) histamine-receptor antagonism. For 2 h of recovery following exercise, arteriovenous glucose differences were assessed from the radial artery and femoral vein, and leg blood flow was measured using Doppler ultrasonography on the common femoral artery. Femoral blood flow following exercise was 65.4 ± 16.4 ml min(-1) lower on the blockade day compared with the control day (P < 0.05). Likewise, glucose delivery was 0.177 ± 0.045 mmol min(-1) lower with blockade (P < 0.05). However, histamine-receptor antagonism produced no consistent effect on leg glucose uptake following exercise, due to high interindividual variability. In conclusion, while oral ingestion of H(1)- and H(2)-receptor antagonists alters postexercise recovery by attenuating vasodilatation, leg glucose uptake is not universally affected in recreationally active individuals.