The present study is the first to investigate the acute metformin intake in athletes on performance and physiological parameters during a typical high-intensity exercise series. We found that metformin does improve performance only on the second bout in a swimming typical series. Physiological and neuromuscular results can explain and support other implications about metformin intake.
Metformin is mainly related to the maintenance of blood glucose (7), thus, it was expected that in pre-training conditions with healthy subjects there were no evident signs of the MET alterations for lactate and blood glucose (10). Although the present study evidences that metformin intake during rest may have a blood glucose lowering effect in swimmers, it is important to emphasize that this effect may have been due to an increase in the blood glucose depletion provided by the effort made in the warm-up.
Metformin intake showed a possible reduced effect on blood glucose followed by a sudden increase during the recovery time (Figure 1). Among the few studies investigating the metformin effects on exercise involving healthy participants, Johnson et al. (10) evidenced that during an aerobic exercise the blood glucose has a slight tendency to reduce when associated with metformin intake, however, this evidence was not significant.
During recovery, it was also possible to note that metformin promoted an "early" recovery behavior by blood glucose when compared to placebo (Figure 1), a situation possibly resulting from a higher uptake of glucose (2, 27, 28). Johnson et al. (10) investigated the metformin effects for healthy subjects, and showed that after an aerobic exercise the metformin had slightly lowered blood glucose levels than the placebo group, however, no difference was found. The difference between the responses for the two studies may be a consequence of the group training status, since athletes have a capillary and blood flow greater than sedentary ones facilitating glucose transport and consequently uptake (29, 30).
Metformin capability to increase the glycolysis rate, consequently increasing lactate production, has already been demonstrated in studies using cell cultures and rats (4, 31). However, as found in the study of Learsi et al. (8), which involved the metformin and exercise in healthy subjects, the present study did not present alterations of this parameter during the rest period.
Despite its behavior at rest, during the typical series, metformin showed a tendency to reduce lactate production from the 2nd to the 8th bout followed by an expressive increase at the end of the series (Figure 2),corroborated by the study of Johnson et al. (10) who verified a similar effect in healthy subjects performing high-intensity exercises after MET uptake. Considering that [Lac-] after supramaximal efforts are associated with glycolysis index (8, 32) and that the typical series model was composed of maximal 50 m maximum efforts, the present study evidence suggest that there was glycolysis reduction during the efforts, contrasting a smaller use of the lactic anaerobic pathway (33).
Lower [Lac-], that characterize discrete decrease of glycolysis (Figure 2) during the series, may indicate that another energetic pathway would have benefited from this metabolic change occurred with similar performance response (Figure 4). In this scenario, the absence of pathway analysis by oxygen consumption limits final conclusions regarding the relationship between the metabolic pathways triggered during and after the typical series. However, a study involving oxygen consumption analysis in healthy individuals after metformin intake evidenced that the anaerobic alactic pathway was potentialized during a supramaximal effort (8).
Learsi et al. (8) showed that metformin improves performance in a supramaximal effort without change in [Lac-] when compared with placebo situation, suggesting the increase of the alactic anaerobic contribution. Despite the intensity of the bouts during the series, the only performance improvement occurred in the second bout accompanied by reduction of [Lac-]. Analyzing this situation, and considering the aerobic participation in the series intervals, it is strongly hypothesized that metformin plays a different role in continuous efforts.
Another important consideration is that reducing the [Lac-] has not been a facilitator for performance improvement, since acidosis increases the hydrogen ion accumulation (H+) reducing the efficiency of the creatine-phosphate system (34). If metformin significantly increased ADP and phosphocreatine (35) resulting in increased creatine kinase, consequently favoring the alactic anaerobic pathway (8), the 50 m performance would have a discreet decrease during the series compared with placebo situation. This hypothesis would be confirmed for two reasons: due to the time of effort in agreement with the production of the energy pathway (50 m bout presented an average time of 30s in this study), and the rest between the bouts (3min) favored the complete resynthesizes of the alactic anaerobic pathway (34). Although these results indicate that the aerobic pathway may undergo alterations after metformin intake, Braun et al. (9) did not find differences in the parameters related to the oxidative pathway.
At the end of the series, a possible increase effect of [Lac-] after metformin intake (1/5/94) was found, while in the 5th minute of the recovery the MET intake had a possible decrease effect on the same parameter (91/8/1). These responses contrast a different behavior after ingestion of the two compounds (evident in Figure 2), which the accumulation and removal process (until the 7th minute) of [Lac-] became "faster" for metformin condition. This behavior becomes even more evident when it is observed that the peak of lactate accumulation after metformin intake occurred at the end of the typical series, whereas after the placebo intake the same physiological situation occurred at the 5th minute (Figure 2).
Although Johnson et al. (10) not investigating the [Lac-] recovery in the short-term, it has been shown that after more than 30 min the [Lac-] recovery is more efficient with the metformin intake. Emphasizing the metformin ability to mediate metabolic changes via AMPK (36), it is suggested that the [Lac-] reduction at the end of an effort may be associated with an increase in the aerobic contribution, however, further investigations involving training in healthy people are required to study the [Lac-] recovery kinetics after metformin intake (10).
Considering the [Lac-],participants and the effort performed on the series (10 bouts with maximum intensity), it is possible that this scenario facilitates the establishment of neuromuscular fatigue (37). Due to the increased blood glucose uptake promoted by metformin, the present study had the complementary objective to verify if the metformin is able to promote better support of the efforts during the series (2). The results indicated that the TSK parameter suffered a possible reduction effect, demonstrating a recovery from the central pathway or, as may have happened in this case, the metformin may have favored the central pathway before the series beginning (38).
In addition to the central pathway recovery, the typical series performed was not able to cause peripheral fatigue in the elbow extensor and knee extensor muscles, considering that the two parameters related to such fatigue (TCTRI and TPK respectively) did not present a significant effect size (38) (Table 1).
The literature lacks research on neuromuscular fatigue in swimming training models; however, studies have shown that a 100 m maximal bout on swimming can generate neuromuscular fatigue and modify the electrical response of upper limbs (39) as well as a 200 m maximum effort (40). There is evidence that the peripheral fatigue process affects lower limbs on a smaller scale in swimming, since much of the swimming propulsion is concentrated in upper limbs (40).
Instead to the above mentioned maximum continuous efforts, the absence of peripheral fatigue from the typical series can be explained by its intermittent characteristics, since the intermittent during a task that requires high-strength levels has the capacity to present lower levels of neuromuscular fatigue for muscles such as the triceps brachii when compared to continuous exercises (41).
The possible increase effect of VAK corroborates the TSK reduction parameter, indicating a facilitation by the metformin for post-activation potentiation of lower limbs, considering that lower limb are less required in swimming and consequently more spared of the fatigue process (40). In addition, metformin increases the recruitment of GLUT-4 (2, 3) which has the function of increasing intramuscular calcium during contraction (42), fundamental for post-activation potentiation to occur and increase muscle voluntary activation (43).
Another potential effect that has been studied for metformin is its ability to inhibit the Mammalian Target of Rapamycin (mTOR) pathway resulting in increased AMPK activity (44). The mTOR pathway plays an important role as a signal of the nervous system under chronic pain conditions, so it is possible that metformin may attenuate sensation of pain (44). Considering the sensations of performing a high-intensity exercise as in the typical series, it was evidenced in two possible (and slight) effects of this drug (after the 1st and 7th bout), indicating that the participants had different fatigue sensations. However, the representation of these scattered results in the general context of the series (two slight effects in 10 moments - Figure 3) are inconclusive and possibly this effect is not associated with fatigue sensations.
Finally, despite the possible effects found for neuromuscular fatigue, blood lactate and glucose, metformin promoted a single performance improvement within the typical series (2nd effort - Figure 4). Due to this was the first study involving metformin for athletes in a typical series in swimming, there is no ecological comparative scientific evidence. Even though the study of Learsi et al. (8) demonstrated a performance improvement in a high-intensity exercise, it is important to note that in the present study, which also used high-intensity efforts, used intermittent efforts with shorter durations. Therefore, the energetic metabolism involved in the task may be different.
Learsi et al. (8) evidenced that the anaerobic alactic pathway could be favored without altering the total anaerobic capacity, however, this would explain a possible improvement in the performance of high-intensity and short duration efforts. In the present study the series used could be strongly favored by the anaerobic alactic pathway in the first efforts, however, no consistent results were found in a general view.
It is concluded that metformin alters metabolic functions in healthy individuals during intermittent exercise and recovery. The results showed that metformin was able to improve the central pathway response before the beginning of the exercise and to increase the voluntary activation; consequently, this neuromuscular alteration increases the post-activation potentiation of skeletal muscle. The neuromuscular mechanism in addition to metformin should still be studied in different situations with greater time-course.
Finally, it was possible to conclude that, besides not altering the fatigue sensation of the participants, the metformin improved performance only in the second bout, but not in the other series on a typical swimming training. In neuromuscular aspects, metformin has effects that can be interpreted as beneficial in a sports setting.
