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J Appl Physiol 103: 1227-1233, 2007. First published July 26, 2007; doi:10.1152/japplphysiol.00027.2007
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Hepatic lactate uptake versus leg lactate output during exercise in humans

H. B. Nielsen,1,2 M. A. Febbraio,3 P. Ott,4 P. Krustrup,5 and N. H. Secher1

Copenhagen Muscle Research Center, Departments of 1Anesthesiology and 2Hepatology, Rigshospitalet, and 5August Krogh Institute, University of Copenhagen, 4Medical Department V, Aarhus University Hospital, Denmark, and 3Cellular and Molecular Laboratory, Baker Heart Research Institute, Melbourne, Australia

Submitted 1 January 2007 ; accepted in final form 18 July 2007


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The exponential rise in blood lactate with exercise intensity may be influenced by hepatic lactate uptake. We compared muscle-derived lactate to the hepatic elimination during 2 h prolonged cycling (62 ± 4% of maximal O2 uptake, VO2max) followed by incremental exercise in seven healthy men. Hepatic blood flow was assessed by indocyanine green dye elimination and leg blood flow by thermodilution. During prolonged exercise, the hepatic glucose output was lower than the leg glucose uptake (3.8 ± 0.5 vs. 6.5 ± 0.6 mmol/min; mean ± SE) and at an arterial lactate of 2.0 ± 0.2 mM, the leg lactate output of 3.0 ± 1.8 mmol/min was about fourfold higher than the hepatic lactate uptake (0.7 ± 0.3 mmol/min). During incremental exercise, the hepatic glucose output was about one-third of the leg glucose uptake (2.0 ± 0.4 vs. 6.2 ± 1.3 mmol/min) and the arterial lactate reached 6.0 ± 1.1 mM because the leg lactate output of 8.9 ± 2.7 mmol/min was markedly higher than the lactate taken up by the liver (1.1 ± 0.6 mmol/min). Compared with prolonged exercise, the hepatic lactate uptake increased during incremental exercise, but the relative hepatic lactate uptake decreased to about one-tenth of the lactate released by the legs. This drop in relative hepatic lactate extraction may contribute to the increase in arterial lactate during intense exercise.

cycling; glucose; liver blood flow

WORKING MUSCLES RELEASE LACTATE, but at a given work load, the arterial concentration reaches a peak in the first minutes of exercise with subsequent disappearance from the circulation (6, 31, 45). During incremental exercise, however, the arterial lactate level increases exponentially with the workload and the concentration of lactate in arterial blood integrates an influence from several organ systems (23). Thus lactatemia is the result of lactate production and utilization, and while nonworking skeletal muscles take up lactate during exercise (4), the muscle mass engaged in exercise influences skeletal muscle lactate uptake (41). In addition, the myocardium (16), the brain (26), and the kidneys (30) remove lactate from blood, but the liver appears to produce lactate during exercise in the dog (53). This finding, however, does not apply to humans as Rowell et al. (45) confirmed the observation (24, 46) that the liver removes lactate during exercise in humans as also reported by Wahren et al. (51) and Ahlborg et al. (4). Lactate is oxidated in both the liver (32) and active muscles (10) and it is suggested that the liver removes half of the lactate produced by the legs even with a 50–70% reduction in hepatic blood flow (45). In response to intense exercise, however, the arteriohepatic venous lactate concentration difference approaches zero when the hepatic venous O2 hemoglobin saturation becomes as low as 10% (35). That finding raised the hypothesis that a marked decrease in hepatic blood flow attenuates hepatic elimination of lactate from the circulation, which is of importance for the increase in arterial lactate during intense exercise. The balance between leg lactate production and hepatic lactate elimination remains, however, to be evaluated during exercise.

In the present study, hepatic uptake of lactate was reevaluated during prolonged exercise (4) followed by a stepwise increase in work intensity to increase lactate production by skeletal muscles with a concomitant marked drop in hepatic blood flow (35). We determined the hepatic lactate uptake as calculated from the product of hepatic blood flow and hepatic lactate concentration differences. The balance between the hepatic lactate uptake vs. the leg lactate output was quantified by the simultaneous determination of leg blood flow and femoral venous to arterial lactate concentration difference.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Seven healthy men (Table 1) participated in the study as approved by the Copenhagen Ethical Committee (KF-01-276/01). Within 2 wk prior to the experiment, each subject performed incremental exercise to determine maximal oxygen uptake (VO2max; 4.0 ± 0.2 l/min; mean ± SE). Two days prior to the experimental trial, the subjects reported to the laboratory and completed 45 min of upright cycling at a workload corresponding to 65% of VO2max. The subjects were provided with a food package (15.6 MJ/day) that consisted of 70% carbohydrate, 15% protein, and 15% fat. They were asked to refrain from strenuous exercise and intake of alcohol, tobacco, and caffeine.


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  		Table 1. Characteristics of the subjects

 
Procedures.   On the day of the experiment, the subjects reported to the laboratory in the morning after a 12- to 14-h overnight fast to limit the influence of portal blood on hepatic exchange of lactate and glucose. It was assumed that a fast limits hepatic glycogen availability, but counterregulatory hormonal responses need to be considered. Under local anesthesia (2% lidocaine), intravascular catheters were inserted into the right cubital vein, the left brachial artery (1.1 mm ID; 20 gauge), and the left femoral vein (7 Fr.; Cook, Denmark). Via the right cubital vein and under x-ray guidance, a hepatic venous catheter (7 Fr.; Cournand) was advanced into a liver vein.

Exercise was performed on a modified cycle ergometer (29). The 2-h protocol included a warm-up for 5 min at 50% VO2max (22) and, thereafter, using a pedaling rate of 60 rpm, the intensity aimed at 70% of VO2max. After the 2 h, the subjects were allowed to rest for 30 min. Then exercise was restarted at the previous intensity with workload increased in increments every 10th min to aim for 80% and 90% of VO2max. The subjects were able to work at 90% of VO2max, but one subject (E) terminated exercise following 5 min and aspiration of arterial blood failed in two subjects (A, E).

Blood samples were collected simultaneously from the brachial artery and the hepatic and femoral veins at rest, every 30th min during prolonged exercise, and after 3 and 9 min at each workload during incremental exercise. Heparinized syringes (QS50; Radiometer, Copenhagen, Denmark) were kept in ice water until analysis for blood gas variables, lactate, glucose, and hemoglobin (ABL 700; Radiometer). Infusion of ICG (0.18 ± 0.02 µM; Cardio-Green; Becton Dickinson, Cockeysville, MD) was initiated 30 min prior to the first blood sample and maintained throughout the experiment using a peristaltic roller pump (Ole Dich, Hvidovre, Denmark). The plasma ICG concentration was determined by high-performance liquid chromatography with subsequent calculation of hepatic blood flow (38). In two subjects (A, C), the ICG and glucose data suggested that the liver venous catheter was dislodged and data were excluded. Leg blood flow was determined by thermodilution (5) in triplicate at rest and every 30th min during prolonged exercise and in the last minute of each workload during incremental exercise. In two subjects (A, C), leg flow data were obtained but aspiration of blood was not possible after prolonged exercise. Data are presented for two legs and the hepatic lactate extraction ratio was calculated as hepatic lactate uptake related to leg lactate output. Leg respiratory quotient (RQ) was the ratio of venous-arterial CO2 content and arteriovenous O2 content difference with blood CO2 content determined using equations by Douglas et al. (21) and Kelman (28).

A Medgraphics CPX/D (St. Paul, MN) was used to determine VO2 and the respiratory exchange ratio (RER). The brachial artery catheter was connected to a sterile disposable pressure transducer (Baxter, Uden, The Netherlands) interfaced with a pressure monitor (Danico Electronic-Dialogue 2000) that displayed heart rate and mean arterial pressure (MAP). Cardiac output was estimated by the model flow method (11).

A one-way ANOVA with repeated measures as the time factor was used to reveal a significant interaction and a post hoc t-test for paired data located specific differences. Variables are expressed as means ± SE and statistical significance was accepted at P < 0.05.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Pulmonary oxygen uptake and blood gas variables.   Exercise increased VO2, heart rate, cardiac output, and RER, with the most marked change noted during incremental exercise where MAP also increased (Table 2). Prolonged exercise reached 62 ± 4% of VO2max and incremental exercise established 71 ± 2% and 84 ± 3% of VO2max at the two last workloads.


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  		Table 2. Cardiovascular and respiratory variables in response to prolonged and incremental ergometer cycling

 
The arterial O2 pressure and hemoglobin O2 saturation did not change significantly during exercise, while the venous values showed a marked drop (Table 3). The concentration of hemoglobin in arterial blood increased. The resting arterial pH, 7.41 ± 0.01, remained unaffected by exercise, whereas in response to incremental exercise, hepatic and femoral venous pH dropped from 7.37 ± 0.01 at rest to 7.31 ± 0.01 and 7.27 ± 0.03, respectively.


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  		Table 3. Blood gases in response to prolonged and incremental ergometer cycling

 
During the most intense exercise, the arterial HCO3– concentration reached a lowest level of 20.1 ± 1.6 mM. During both prolonged and incremental exercise, the arterial CO2 pressure decreased and femoral venous CO2 pressure increased, whereas the hepatic venous CO2 pressure remained unaffected by exercise. At rest, arterial-femoral venous O2 content difference was 4.1 ± 0.1 ml/dl with an increase to 13.7 ± 0.2 ml/dl (P < 0.05) during prolonged exercise and 14.5 ± 0.6 ml/dl (P < 0.05) at the heaviest workload. Likewise, the resting arterial-hepatic venous O2 content difference increased from 4.4 ± 0.3 ml/dl at rest to 12.1 ± 0.8 ml/dl (P < 0.05) during prolonged exercise and to 13.5 ± 0.9 and 16.1 ± 0.4 ml/dl (P < 0.05), respectively, during the last two workloads of incremental exercise.

Hepatic and leg blood flow.   In response to prolonged exercise, hepatic blood flow remained at the resting level until 1.5 h of cycling where it decreased by 20 ± 7% (P < 0.05; Fig. 1). In the recovery between the two exercise bouts, hepatic blood flow increased above the resting level. When exercise was recommenced, hepatic blood flow decreased with each increment in intensity to reach the lowest value of 0.30 l/min at the workload corresponding to 84% of VO2max. With the enlargement of the arteriohepatic venous O2 difference during exercise, the hepatic O2 uptake increased during both prolonged and incremental exercise. When flow was lowest at the heaviest workload, however, the hepatic O2 uptake was not significantly different from the resting level (Table 4).


Figure 1
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  		Fig. 1. Hepatic blood flow and blood flow for 2 legs at rest and in response to prolonged ergometer cycling (leg O2 uptake 1,764 ± 148 ml/min) and, following a 30-min recovery period (rec), incremental intensity (leg O2 uptake 2,236 ± 226 and 2,770 ± 209 ml/min) until exhaustion (inc). Values are means ± SE. *Different from rest, P < 0.05.

 

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  		Table 4. Hepatic and leg lactate and glucose in response to prolonged and incremental ergometer cycling

 
Exercise increased leg blood flow and during prolonged exercise it remained at similar levels throughout the 2-h cycling period (Fig. 1). In the recovery, leg blood flow dropped to the preexercise value and during incremental exercise, there was a marked increase in leg blood flow, reaching the highest level at 84% of VO2max. With the change in arteriofemoral venous O2 difference, the leg O2 uptake demonstrated a 40-fold increase during prolonged exercise and a 60-fold increase during incremental exercise (Table 4). Likewise, the leg RQ increased with exercise and the changes in leg O2 uptake were correlated to VO2 (Fig. 2).


Figure 2
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  		Fig. 2. Pulmonary and leg O2 uptake during exercise.

 
Glucose and lactate.   In response to prolonged exercise, arterial and femoral venous glucose decreased progressively to the lowest value after 2 h of cycling with similar levels during incremental exercise (Table 5). Hepatic venous glucose increased during exercise with the highest level at the third workload during incremental exercise. The arterial-femoral venous glucose difference increased ~0.4 mM during prolonged exercise and 0.3 mM during incremental cycling (Fig. 3) and, therefore, leg glucose uptake was markedly increased. During exercise, the hepatic venoarterial glucose difference increased progressively during exercise. Thus hepatic glucose output doubled compared with rest and when hepatic blood flow was lowest at the heaviest workload, hepatic glucose output approached the preexercise level (Table 4).


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  		Table 5. Blood concentrations of lactate and glucose in response to prolonged and incremental ergometer cycling

 

Figure 3
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  		Fig. 3. Glucose difference (top) is the hepatic venoarterial ({circ}) and the arterial-femoral venous (bullet) lactate concentration differences. Lactate difference (bottom) is femoral venoarterial (bullet) and arterial-hepatic venous ({circ}) lactate concentration differences. Values are means ± SE. *Different from rest, P < 0.05.

 
In the first 30 min of prolonged exercise, arterial lactate was close to 4 mM and, as exercise continued, it dropped to about 2 mM (Table 5). During incremental exercise, the arterial lactate reached a maximum of 10.4 mM. Hepatic and femoral venous lactate remained lower and higher, respectively, than the levels in the artery. During exercise, the femoral venoarterial lactate difference increased (Fig. 3) and, therefore, also the leg lactate output increased (Table 5). After 2 h exercise, there was a trend toward a lower leg lactate output compared with the first part of exercise (Table 4). In contrast, during incremental exercise, the leg lactate output was almost threefold higher than during prolonged exercise (P < 0.05).

During prolonged exercise, the change in the average arterial-hepatic venous lactate difference failed to reach statistical significance (Table 3). In one subject, hepatic lactate uptake decreased from 0.11 mmol/min at rest to –0.44 mmol/min after the first 30 min of exercise and in the following 1.5 h of cycling, the hepatic lactate uptake inclined to –0.08 mmol/min. During prolonged exercise in the other subjects, the hepatic lactate uptake ranged from 0.16 to 1.61 mmol/min. With incremental exercise, the arterial-hepatic venous lactate difference reached the highest level and, as hepatic blood flow decreased, the average hepatic lactate uptake was ~20–25% higher than during prolonged exercise (Table 5).

The rise in arterial lactate correlated to the leg lactate release (r2 = 0.28, P < 0.05) and to the liver lactate uptake (r2 = 0.38, P < 0.05). During prolonged exercise, the difference between the leg lactate output and the hepatic lactate uptake was small but it increased during incremental exercise (Fig. 4). When the arterial lactate was low, there was an almost linear relation between leg lactate output and hepatic lactate uptake (Fig. 5). At arterial lactate levels ~4 mM, leg lactate output is not followed by a similar increase in hepatic lactate uptake. Thus during prolonged exercise, the hepatic lactate uptake was about half the leg lactate output, but during incremental exercise, that fraction decreased to 12%.


Figure 4
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  		Fig. 4. Lactate overflow is leg lactate output minus hepatic lactate uptake at rest and during constant and incremental exercise aimed at 80% and 90% of maximal O2 uptake. The average arterial lactate is noted. Values are means ± SE. *Different from rest, P < 0.05.

 

Figure 5
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  		Fig. 5. Corresponding values for leg lactate output and hepatic lactate uptake. The average arterial lactate is noted for each symbol. Values are means ± SE.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
It was an early observation that, after an initial increase in blood lactate at the onset of exercise, blood lactate declines (6, 31), reflecting both a drop in lactate appearance and even a net lactate uptake by the working muscles (14). During prolonged exercise, the present study demonstrates that arterial lactate drops as lactate release from the working muscles decreases, whereas the liver elimination of lactate is maintained throughout the 2-h exercise period. With increasing work rate, lactate release by the legs was markedly increased, but even with accelerated hepatic lactate uptake, the liver took up only about one-tenth of the leg lactate produced by the legs compared with 25% during prolonged exercise. This drop in hepatic extraction ratio may contribute to the rise in arterial lactate when exercise becomes intense.

Hepatic blood flow.   Estimation of liver blood flow is based on the assumption that ICG is eliminated exclusively by hepatic tissue (37). As in previous studies, extraction of ICG was representative of a single hepatic lobe (45) and once the arterial ICG concentration is constant, this level reflects total hepatic removal. The fractional arterial clearances of ICG can also be applied to estimate hepatic blood flow (44). Independently of the chosen technique, hepatic blood flow is slightly reduced during low-intensity exercise (2) with a marked reduction in response to intense exercise (35, 45), often described as an inverse relation to heart rate (43).

In the present study, a two-third reduction in hepatic blood flow is among the most marked reduction reported during exercise in humans. With more intense sympathetic activation and a cardiac output above 30 l/min, ICG clearances may even approach zero (34). Thus, during exercise, there is a reciprocal relationship between liver and leg blood flow. At rest, hepatic blood flow represented 19% of cardiac output and it decreased to 2% during maximal exercise supporting that splanchnic organs act as a "blood donor" to the systemic circulation (27).

Leg blood flow.   It is well established that muscular activity increases blood flow to the working muscles and the thermodilution technique according to Andersen and Saltin (5) is used to estimate leg blood flow during cycling (39), arm cranking (49), and knee extension exercise (40). The leg blood flow determined in the present study reached a level similar to that reported by others during incremental cycling (33) and linearity was observed with work rate as reflected in VO2 supporting the work by Richardson et al. (41). However, there appeared to be no leveling off in leg blood flow during the incremental exercise (33), probably because a maximal VO2 was not established.

Lactate.   At rest there is a release of lactate by the legs (4) and although the hepatic lactate uptake is lower than the leg lactate output, the level of lactate in arterial blood is usually kept below 1 mM in healthy subjects. Exercise distorts this stability for blood lactate as observed in the last century (6, 25, 31, 45) due to a marked increase in lactate production by skeletal muscles (10). Yet arterial lactate decreased with time during prolonged exercise as reflected in the increase of leg lactate output within 30 min of exercise onset but decline as exercise continued (48). A Stainsby effect (47) of transient muscle lactate release at exercise onset followed by net uptake of lactate from the blood by working muscle is observed in men exercising both at altitude (13, 15) and at sea level (3, 13, 51). Thus during exercise in altitude, arterial lactate remains high despite a marked drop in limb lactate output and it is proposed that tissues other than working skeletal muscle contribute to the circulating lactate load (14).

The liver releases lactate in the working dog (53) and this finding is not reproduced during exercise in humans (3, 45, 51). Previously, we reported that the arteriohepatic venous lactate concentration difference approached zero when the hepatic venous O2 hemoglobin saturation was below 10% (35) and during incremental exercise in the present study, all subjects demonstrated net hepatic lactate uptake. During prolonged exercise, however, in one subject, the liver venous lactate was 0.34 mM higher than in the artery and after 2 h exercise, that difference was narrowed to 0.08 mM. This supports the observation by Wasserman et al. (53), but the net hepatic lactate release appears to be much higher during exercise in animals. In addition, arterial blood lactate integrates the influence from several organ systems (23) and the "lactate shuttle hypothesis" (12) may work differently in humans and animals.

In response to exercise, the rate of whole body lactate appearance is much higher than lactate disappearance (10) and throughout prolonged exercise, the hepatic lactate uptake remained at ~0.8 mM. An interesting observation is that the difference between the hepatic lactate uptake and leg lactate output decreased from ~3 mM within the first 30 min to ~2 mM in the remaining period. We did not measure lactate uptake by resting skeletal muscles, which may approach 2 mM during one-legged exercise (41). However, during cycling, the muscle mass is larger than during knee extension and, therefore, when leg lactate output was markedly increased in response to cycling and the liver failed to accelerate its lactate uptake to the same extent it was produced by the legs, the arterial lactate increased. It may be that with the combination of hepatic hypoperfusion and marked lactate release by the skeletal muscles, the hepatic lactate uptake reaches a maximum or it levels off. In support, at the heaviest workload, the hepatic O2 uptake approached the preexercise level and previous work suggests a reduction in available sinusoids (35). Thus the hepatic lactate uptake appears to reach an upper limit at an arterial lactate concentration of ~4 mM and this so-called "anaerobic threshold" (1) may represent a lactate extraction threshold.

Glucose.   In response to exercise, plasma glucose concentration remains relatively stable (17). During prolonged exercise in particular, relative hypoglycemias may arise (19) despite markedly increased rate of glucose appearance (8, 9, 29). Thus, during prolonged exercise, muscle glucose uptake increases with time (4) and it is estimated that glucose uptake per kilogram of working muscle is ~0.3 mmol·kg–1·min–1 with cycling and 0.5 mmol·kg–1·min–1 in response to one-legged knee extension (41). With an estimated 10 kg muscle engaged in two-legged cycling, the leg glucose uptake obtained in our study appears to be a little higher than previously reported and leg glucose uptake is not accelerated as exercise intensity increases. During prolonged exercise, hepatic glucose output is also increased with time and with an estimated 1.5 kg hepatic tissue, the glucose output per kilogram is about fivefold higher than the leg uptake. As for the muscle, it appears that the hepatic glucose output is not increased with raised exercise intensity and it may even decrease as supported by a drop in hepatic metabolic rate.

The level of glucose in arterial blood is the balance between glucose utilization and total glucose production. With respect to lactate, the Cori cycle is described as a process in which lactic acid production in skeletal muscle is released into the blood and brought to the liver and converted into glucose/glycogen for subsequent delivery to the muscle (18). Also the kidney is considered to produce glucose from lactate, although that does not appear to be the case during exercise in humans (51). Based on venoarterial differences, it is not possible to evaluate the relative contribution of hepatic glycogenolysis and hepatic gluconeogenesis and the mechanisms for regulating arterial glucose and the liver glycogen level were not addressed. In addition, we can only speculate on the fate of lactate. Previous studies using isotope tracers suggest that with increasing exercise intensity, one-half of whole body lactate disappearance is explained by active limb lactate uptake (7) and oxidation is the major fate of whole body lactate disposal (10).

In general, hepatic gluconeogenesis increases during moderate and high-intensity exercise (50) and, assuming that 2 mol of lactate are used for the production of 1 mol glucose, the contribution of lactate for hepatic glucose production increased from {approx}10% during prolonged exercise to {approx}30% during incremental exercise. It should be considered that during prolonged exercise, hepatic glycogen content might decrease, whereby gluconeogenesis becomes more important for hepatic glucose production (52). With a lactate clamp, it is demonstrated that during moderate exercise gluconeogenesis increases (42) and the enhanced hepatic lactate uptake may even spare hepatic glycogenolysis (32). With the increase in gluconeogenic precursors during incremental exercise, however, hepatic lactate uptake is not accelerated from what could be expected, as lactate uptake follows Michaelis-Menten kinetics (20, 36). Thus, in line with previous suggestions (35, 50), a reduction of hepatic blood flow to 0.30 ml/min due to redistribution of cardiac output to working muscles may limit hepatic gluconeogenesis.

Conclusion.   During prolonged exercise, a balance between leg lactate release and hepatic lactate uptake is established and arterial lactate is maintained below 4 mM. During incremental exercise, however, the hepatic lactate uptake is not accelerated to the same extent as leg lactate release and arterial lactate increases above the 4 mM level.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This paper was prepared with funding from the Danish Research Agency (the Strategic Programme for Young Scientists).


   ACKNOWLEDGMENTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
We thank anesthesia nurse P. Nissen for expert technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. Bay Nielsen, Dept. of Anesthesia 2041, Rigshospitalet, Blegdamsvej 9, 2100 København Ø, Denmark (e-mail: hbay{at}vip.cybercity.dk)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 REFERENCES
 

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