Decreased Blood Glucose and Lactate: Is a Useful Indicator of Recovery Ability in Athletes?

During low-intensity exercise stages of the lactate threshold test, blood lactate concentrations gradually diminish due to the predominant utilization of total fat oxidation. However, it is unclear why blood glucose is also reduced in well-trained athletes who also exhibit decreased lactate concentrations. This review focuses on decreased glucose and lactate concentrations at low-exercise intensity performed in well-trained athletes. During low-intensity exercise, the accrued resting lactate may predominantly be transported via blood from the muscle cell to the liver/kidney. Accordingly, there is increased hepatic blood ow with relatively more hepatic glucose output than skeletal muscle glucose output. Hepatic lactate uptake and lactate output of skeletal muscle during recovery time remained similar which may support a predominant Cori cycle (re-synthesis). However, this pathway may be insu cient to produce the necessary glucose level because of the low concentration of lactate and the large energy source from fat. Furthermore, fatty acid oxidation activates key enzymes and hormonal responses of gluconeogenesis while glycolysis-related enzymes such as pyruvate dehydrogenase are allosterically inhibited. Decreased blood lactate and glucose in low-intensity exercise stages may be an indicator of recovery ability in well-trained athletes. Athletes of intermittent sports may need this recovery ability to successfully perform during competition. Keywords: aspartate transaminase; Cori cycle; hepatic blood ow; oxaloacetate; phosphoenolpyruvate carboxykinase; pyruvate dehydrogenase 1. Introduction Clinical physicians and sports scientists have used lactate threshold (LT) tests for over fty years because their application

low-intensity exercise stages may be an indicator of recovery ability in well-trained athletes. Athletes of intermittent sports may need this recovery ability to successfully perform during competition. Keywords: aspartate transaminase; Cori cycle; hepatic blood ow; oxaloacetate; phosphoenolpyruvate carboxykinase; pyruvate dehydrogenase 1. Introduction Clinical physicians and sports scientists have used lactate threshold (LT) tests for over fty years because their application is considered extremely useful for recommendations on individual exercise intensity in cardiac patients and trained athletes [1,2]. Endurance athletes regularly undergo these tests in order to control individual exercise intensity during endurance training [1,3–6]. Both respiratory and metabolic parameters are commonly utilized to identify the anaerobic threshold [1] and oxygen uptake (VO2) during exercise performance in uenced by the percentage of maximal oxygen uptake (VO2max) at LT. The workout test is performed either on a bicycle ergometer or on a treadmill applying di erent steps [1,7]. The ramp test is applied to determine VO2maxand lactate values at each step in order to analyze the metabolic system and physiological performance [8]. The number of scienti c studies on LT has increased enormously and among the diagnostics of endurance performance in sports, submaximal exercise is probably one of the most relevant [1,2,5,9–13]. For instance, increased exercise intensity at four millimoles per liter lactate was commonly observed as the lactate threshold in Int. J. Environ. Res. Public Health2020,17, 5470; doi:10.3390 /ijerph17155470 /journal/ijerph

Int. J. Environ. Res. Public Health2020,17, 5470 2 of 16 endurance-trained athletes, and this value is highly associated with the potential maximal lactate steady state level (MLSS) [4,14,15]. A rightward shift of the exponential lactate curve can generally be interpreted as improved endurance capacity [2,16–18]. Furthermore, validated LT concepts such as aerobic-anaerobic transition using lactate and gas exchange parameters were applied and re ned by several scientists [2,4,10,12,18–24]. To measure the exercise capacity, numerous studies have been focused on altered blood glucose concentrations following moderate-to-high-intensity exercise in LT tests. The metabolic changes in blood glucose concentration during low-intensity exercise in LT test are not analyzed [2,4,14,15,18–23,25–33]. Glucose 6-phosphate, supplied through breakdown of muscle glycogen and blood glucose, is metabolized to lactate and re-synthesized to adenosine triphosphate (ATP) by substrate-level phosphorylation reactions [34]. The blood glucose of endurance-trained athletes is decreased during the early stages of LT testing while blood lactate concentration (below lactate baseline concentration; LTAer or<two millimoles per liter) is also reduced. This exercise area is commonly referred to as regenerative endurance training [2]. In these low exercise stages, it seems likely that blood lactate concentrations gradually decrease as a result of the predominance of total fat oxidation [2,14,25–27]. In terms of energy metabolism, fat is also used as an energy source and represents the main energy source in moderate exercise under aerobic conditions. However, fat oxidation cannot predominantly be used to meet the energy demand during high-intensity exercise. Under this condition, carbohydrate oxidation represents the primary source of energy [25,35]. In turn, at low-intensity, triglycerides in adipocytes are hydrolyzed into glycerol and free fatty acids (lipolysis) which are then converted into acetyl-CoA by ß-oxidation in the mitochondria. At low-intensity exercise levels of 25% VO2max, plasma fatty acids are delivered for energy production [25,36]. In light of this, it is understandable why lactate values in blood begin to decrease at this exercise intensity as more pyruvate and lactate are used aerobically than are generated via anaerobic glycolysis [14]. However, the reduction in blood glucose during low-intensity exercise is difficult to explain. Blood glucose concentrations are usually increased incrementally with

delivered for energy production [25,36]. In light of this, it is understandable why lactate values in blood begin to decrease at this exercise intensity as more pyruvate and lactate are used aerobically than are generated via anaerobic glycolysis [14]. However, the reduction in blood glucose during low-intensity exercise is difficult to explain. Blood glucose concentrations are usually increased incrementally with exercise from low to high intensity because carbohydrate metabolism partly contributes to aerobic glycolysis during low-intensity exercise [ The aim of this literature review was to describe possible relationships between exercise intensity, glucose and lactate at the low-intensity exercise stages of the LT test. To date, it is unclear why blood glucose is reduced while lactate values are also decreased during low-intensity exercise. Therefore, comprehensive aspects of the underlying physiological and molecular biologic background are considered. We suggest that decreased blood glucose and lactate at low-intensity exercise (LT test) are relevant signals for the recovery ability of well-trained athletes in intermittent and endurance sports. 2. Materials and Methods Literature studies were performed using online data bases including Scopus, PubMed (Medline) and Web of Science and published articles were retrieved (1929–2019). Major keywords regarding lactate threshold test (“LT”, “lactate threshold”, “MLSS”, “endurance”, “aerobic”, “anaerobic” and “recovery”) and physiological and biochemical reactions occurring during low-intensity exercise (“glycolysis”, “gluconeogenesis”, “glycogenesis”, “lactate metabolism”, “glucose metabolism”, “MCT”, “fat oxidation”, “oxaloacetate”, “pyruvate”, “AMPK”, “hepatic blood ow”, “skeletal muscle blood ow”, “skeletal muscle lactate output” and “hepatic lactate uptake”) were used in diverse combinations. Original full-text articles and reviews in English language published in scienti c journals were included. Articles describing human and animal species were included. Conference articles, posters and studies with information overlapping with another publication were excluded. Based on a review of overlapping articles, the most recent or the most comprehensive articles were selected. After the initial searches identi ed articles, of which 167 were screened from the aforementioned databases. 30 articles were excluded because of unavailable full-text articles (11) and absence of speci c data related to blood glucose and lactate without exercise (19). Of these, 115 articles were screened for eligibility, while

the most recent or the most comprehensive articles were selected. After the initial searches identi ed articles, of which 167 were screened from the aforementioned databases. 30 articles were excluded because of unavailable full-text articles (11) and absence of speci c data related to blood glucose and lactate without exercise (19). Of these, 115 articles were screened for eligibility, while 22 were excluded due to lack of useful data related to exercise physiology and

Int. J. Environ. Res. Public Health2020,17, 5470 3 of 16 clinical features (Figure). One author (W.-H.Y.) reviewed the titles and abstracts of studies and the remaining 167 articles using the foregoing search strategy. Another author (H.P.) reviewed the article inclusion/exclusion criteria. Eligible articles were retrieved and independently assessed by two authors (W.-H.Y. and H.P.). The disagreement between authors over the eligibility of remaining articles was resolved through discussion with other collaborating authors (M.G. and O.H.). Furthermore, two authors (W.-H.Y. and H.P.) independently extracted data from articles based on study features and populations, type of intervention, measurement procedure and outcomes. Figure 1.Flow chart outlining the literature search strategy. 3. Utilization of Fat Oxidation During Low-Intensity Exercise The entire energy system, including phosphagens, glycolysis and oxidative phosphorylation, is simultaneously used during all levels of exercise intensity. In general, it seems important which energy system is predominantly used during di erent exercise intensities and exercise volumes. The energy storage of human fat is e ectively unlimited during exercise [37]. Accordingly, one gram of fat provides about 40.79 kJ of energy. Very lean individuals of 70 kg and 10% body fat approximately have 285.56 kJ of endogenous fat energy [38]. With regard to low-intensity exercise, the oxidative metabolism from carbohydrate and fat is predominant. Adipocytes store large amounts of energy in the form of

Int. J. Environ. Res. Public Health2020,17, 5470 4 of 16 triglycerides which amount to 200–625 Megajoule (MJ) in humans with normal body compositions of 10–30% body fat [25,36]. The energy expenditure derived from fat comes from various sources including plasma fatty acids from lipolysis in adipose tissue, fatty acids liberated from hydrolysis of circulating very low density lipoprotein (VLDL)-triacylglycerol and fatty acids from lipolysis of triacylglycerol located in lipid droplets in the skeletal muscle [39]. Plasma triglycerides are used as a crucial energy source in the muscle. However, when triglyceride in muscle cells are catalyzed by lipoprotein lipase, their contribution to energy demands during high-intensity exercise is limited [40]. During low-intensity exercise (25% VO2max), overall energy is obtained from plasma fatty acids with an additional small contribution from blood glucose. The rate of plasma fatty acid oxidation is similar to the rate of fatty acid oxidation (26 mol kg 1 min 1 ) in endurance-trained athletes. Furthermore, an increase in exercise intensity from 25% to 85% VO2maxresulted in a progressive decline of fatty acid oxidation along with a proportional reduction of its concentration in blood [25]. This was due to insu cient transport of out owing blood and albumin from adipose tissue into the systemic circulation [36,41]. 4. Lactate, Glucose, Enzymatic Responses and Cori Cycle During Exercise Lactate is produced during glycolysis, which is one of the metabolic pathways through which glucose can be utilized to provide energy. Lactate production from glycolysis occurs in muscle when exercise intensity increased [27]. Anaerobic conditions were not essential for the production of lactate in animal experiments (tail shaker muscle; western diamondback rattlesnake) [42] thus indicating that energy systems (phosphagen, glycolytic and oxidative) started to work simultaneously while the dissociation between lactate and hypoxic or anoxic conditions was orderly conformed [27]. Another study using the same model in ischemic and normoxic situations showed that increased rates of glycolysis could occur independently of O2[43]. Such muscle conditions indicated the capability for exercise without fatigue [27] because of high blood ow rates that allowed the rapid turnover of H + and lactate within the cell (and

or anoxic conditions was orderly conformed [27]. Another study using the same model in ischemic and normoxic situations showed that increased rates of glycolysis could occur independently of O2[43]. Such muscle conditions indicated the capability for exercise without fatigue [27] because of high blood ow rates that allowed the rapid turnover of H + and lactate within the cell (and also other metabolites that may be involved in the fatigue process) [27,44]. These results indicated that, in addition to lactate production during anoxic or hypoxic situations, lactate was also produced as a metabolite due to adequate oxygenation [27]. Formerly, the understanding of lactate physiology was that lactate transport took place through simple di usion (e.g., in the bloodstream) from cellular compartments to the blood. Increased lactate concentrations were believed to be a consequence of glycolytic ux rates [45–48]. In addition, previous studies had shown that three pathways were involved in lactate transport in red blood cells (RBC)—(i) H + coupled transporter, (ii) band 3 protein Cl /HCO3 -mediated exchange with inorganic anions and (iii) passive di usion of lactate across the lipid bilayer [49–51]. Nowadays, monocarboxylate transport (MCT) proteins (14 isoforms in total) are known to play critical roles in lactate transport. Cluster of di erentiation 147 (CD147) functions as an ancillary protein that chaperones MCT1 and MCT4 to the cell membrane (muscle, red blood cell and liver). Human, rat and horse muscles express MCTl and MCT4. Both MCT1 and MCT4 need of an ancillary protein CD147 for their activity [52–54]. MCT1 and 4 are the predominant MCT transporters in human skeletal muscle while MCT2 is prominently expressed in the liver and brain [55,56]. MCT1 is coordinately expressed with isoforms of lactate dehydrogenase (LDH). High levels of MCT1 and LDH are found in oxidative muscle bers [57]. In addition, MCT1 is the most important protein for lactate transport into or out of RBC [58,59]. In contrast, the low a nity transporter MCT4 was shown to be relevant for the net export of lactate from the cell which was predominantly expressed in glycolytic type IIA bers [60]. MCTs transfer lactate into

are found in oxidative muscle bers [57]. In addition, MCT1 is the most important protein for lactate transport into or out of RBC [58,59]. In contrast, the low a nity transporter MCT4 was shown to be relevant for the net export of lactate from the cell which was predominantly expressed in glycolytic type IIA bers [60]. MCTs transfer lactate into and out of cells and other organs such as liver, kidney, heart and brain [61,62]. These are now known as lactate shuttle mechanisms. The intracellular lactate shuttle mechanism is based on mitochondria-localized LDH (mLDH) for the re-synthesis between lactate and pyruvate [63]. During lactate production at rest and during submaximal exercise, pyruvate is converted to lactate by lactate dehydrogenase (LDH and mLDH) reaction. In addition, lactate can be reversibly converted to pyruvate by the intracellular lactate shuttle mechanisms [27,61,64].

Int. J. Environ. Res. Public Health2020,17, 5470 5 of 16 The liver is capable of eliminating lactate during exercise [65,66]. The Cori cycle, refers to the metabolic pathway of lactate-produced by anaerobic glycolysis in the muscle cells-moved to the liver and converted to glucose in order to ultimately return to the muscles [67]. Intensive exercise may impair the Cori cycle resulting in increased blood lactate concentrations which can be a ected by decreased hepatosplanchnic blood ow [68]. Nielsen et al. [69] reported that arterial lactate was decreased because of reductions in lactate release from the working muscles during prolonged exercise (2 h and ~70% of VO2max, respectively). In contrast, liver clearance of lactate was maintained during a 2 h exercise phase. Lactate release by legs was signi cantly increased with increased work rate (~90% of VO2maxduring 20 min). However, the uptake of hepatic lactate constituted only one-tenth of the leg lactate production compared with 25% during prolonged exercise, while hepatic blood ow was markedly decreased, and leg blood ow increased. This reduction in hepatic extraction ratio may in uence the rise in arterial lactate concentrations when exercise intensity is increased. On the other hand, leg lactate output and hepatic lactate uptake were similar (0.5 0.3 and 0.55 0.25 mmol min 1 , respectively) and the hepatic blood ow was accordingly increased during a recovery period (20 min) between exercises [69]. This study result showed that a two-third reduction in hepatic blood ow was among the most distinct changes during high-intensity exercise. With more intensive sympathetic activation and a cardiac output of more than 30 L min 1 , indocyanine green dye (ICG) eliminations may even approximate zero [70]. Therefore, a reciprocal relationship existed between liver and leg blood ow. During resting condition, hepatic blood ow was 19% of cardiac output which decreased to 2% during high-intensity exercise. This indicates that splanchnic organs contribute as a “blood donor” to the systemic circulation [69,71]. Glucose utilization and total glucose production are balanced by the concentration of glucose in arterial blood. As described above, the Cori cycle is responsible for lactate to glucose

resting condition, hepatic blood ow was 19% of cardiac output which decreased to 2% during high-intensity exercise. This indicates that splanchnic organs contribute as a “blood donor” to the systemic circulation [69,71]. Glucose utilization and total glucose production are balanced by the concentration of glucose in arterial blood. As described above, the Cori cycle is responsible for lactate to glucose conversion in the liver [67]. However, if the hepatosplanchnic blood ow reaches a minimum, resulting in a reduction in hepatic venous O2saturation to 6%, the contribution of the Cori cycle to glucose production appears to decrease during exercise [68]. During prolonged exercise, relative hypoglycemia may emerge although the rate of glucose appearance is signi cantly increased [72–75]. Therefore, muscle glucose uptake can be increased with time during prolonged exercise [65,69]. During high-intensity exercise, leg glucose uptake was increased while hepatic glucose output was signi cantly decreased (6.2 1.3 and 1.9 0.41 mmol min 1 , respectively). Furthermore, another study outcome showed that when exercise intensity was higher than 50% of VO2maxthe rate of gluconeogenesis was decreased because of the reduced hepatic blood ow [45]. In comparison to these levels, leg glucose uptake was markedly lower than hepatic glucose output during rest and recovery times (0.3 0.1, 1.9 0.5 and 1.55 0.23, 2.34 0.75 mmol min 1 , respectively) [69]. During recovery, despite hepatic blood ow being relatively increased, the Cori cycle (gluconeogenesis) may be insu cient to provide the needed glucose for maintaining blood glucose concentrations. The mechanism of attenuation of gluconeogenesis by sympathetic nervous system and upregulation of glycogenolysis still remains unclear [76,77]. The hepatic artery is sustained with - and -receptors [78,79]. A high level of epinephrine could cause an increase in hepatic glucose production, partly owing to an increased supply of gluconeogenic substrates such as alanine—and partly associated with a direct action on the liver cells [80]. In contrast, exercise with -receptor blockade led to decreased hepatic uptake of gluconeogenic precursors, decreased lactate uptake and increased glucose output [76]. Furthermore, interleukins were released from active muscle during exercise and these are relevant for hepatic glucose production [77].

an increased supply of gluconeogenic substrates such as alanine—and partly associated with a direct action on the liver cells [80]. In contrast, exercise with -receptor blockade led to decreased hepatic uptake of gluconeogenic precursors, decreased lactate uptake and increased glucose output [76]. Furthermore, interleukins were released from active muscle during exercise and these are relevant for hepatic glucose production [77]. Decreased hepatosplanchnic blood ow may reduce the available number of hepatic sinusoids. Norepinephrine decreases the hepatic blood volume—even the plasma volume in hepatic sinusoids may be in uenced [81]. Blood ow reductions of 30–40% during hemorrhage in the pig resulted in a reduction of hepatic norepinephrine uptake which induced a partial sinusoidal collapse [82]. In addition, Nielsen et al. [68] showed that a decreased intrinsic hepatic elimination of ICG during exercise caused a reduction of active sinusoidal area in human.

The study examines the relationship between blood glucose, lactate, and recovery in athletes during low-intensity exercise.