International  Journal  of
Environmental Research
and Public Health
Review
Decreased Blood Glucose and Lactate: Is a Useful
Indicator of Recovery Ability in Athletes?
Woo-Hwi Yang 1,*
, Hyuntae Park 2,*
, Marijke Grau 3 and Oliver Heine 4
1
Graduate School of Sports Medicine, CHA University, Seongnam-si, Gyeonggi-do 13503, Korea
2
Department of Health Care and Science, College of Health Science, Dong-A University, Busan 49315, Korea
3
Department of Molecular and Cellular Sports Medicine, Institute of Cardiovascular Research and Sports
Medicine, German Sport University Cologne, 50933 Cologne, Germany; m.grau@dshs-koeln.de
4
Olympic Training Centre Rhineland, 50933 Cologne, Germany; heine@osp-rheinland.de
*
Correspondence: ywh1235@cha.ac.kr (W.-H.Y.); htpark@dau.ac.kr (H.P.)
Received: 9 July 2020; Accepted: 28 July 2020; Published: 29 July 2020


Abstract: 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 ﬂow 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 insuﬃcient 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
ﬂow;
oxaloacetate;
phosphoenolpyruvate carboxykinase; pyruvate dehydrogenase
1. Introduction
Clinical physicians and sports scientists have used lactate threshold (LT) tests for over ﬁfty 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 inﬂuenced 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
diﬀerent steps [1,7].
The ramp test is applied to determine VO2max and lactate values at each step in order to
analyze the metabolic system and physiological performance [8]. The number of scientiﬁc 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 Health 2020, 17, 5470; doi:10.3390/ijerph17155470
www.mdpi.com/journal/ijerph
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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 reﬁned 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 exercise from low to high intensity because
carbohydrate metabolism partly contributes to aerobic glycolysis during low-intensity exercise [14,25].
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 ﬂow”,
“skeletal muscle blood ﬂow”, “skeletal muscle lactate output” and “hepatic lactate uptake”) were
used in diverse combinations. Original full-text articles and reviews in English language published
in scientiﬁc 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 identiﬁed articles, of which 167 were screened from the aforementioned
databases. 30 articles were excluded because of unavailable full-text articles (11) and absence of speciﬁc
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
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clinical features (Figure 1). 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 diﬀerent exercise intensities and exercise volumes. The energy
storage of human fat is eﬀectively 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
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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 µmol·kg−1·min−1) in endurance-trained athletes.
Furthermore, an increase in exercise intensity from 25% to 85% VO2max resulted in a progressive decline
of fatty acid oxidation along with a proportional reduction of its concentration in blood [25]. This was
due to insuﬃcient transport of outﬂowing 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 ﬂow 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 diﬀusion (e.g., in the bloodstream) from cellular compartments to the blood. Increased lactate
concentrations were believed to be a consequence of glycolytic ﬂux 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 diﬀusion 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 diﬀerentiation 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 ﬁbers [57]. In addition, MCT1 is the most important protein for lactate transport
into or out of RBC [58,59]. In contrast, the low aﬃnity transporter MCT4 was shown to be relevant
for the net export of lactate from the cell which was predominantly expressed in glycolytic type IIA
ﬁbers [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].
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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 aﬀected by
decreased hepatosplanchnic blood ﬂow [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 signiﬁcantly increased with increased work rate (~90%
of VO2max during 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 ﬂow was
markedly decreased, and leg blood ﬂow increased. This reduction in hepatic extraction ratio may
inﬂuence 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 ﬂow was accordingly increased during a recovery period (20 min)
between exercises [69]. This study result showed that a two-third reduction in hepatic blood ﬂow 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 ﬂow. During resting condition, hepatic blood ﬂow 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 ﬂow reaches a minimum, resulting in a reduction in
hepatic venous O2 saturation 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 signiﬁcantly 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 signiﬁcantly 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 VO2max the rate of gluconeogenesis was decreased because of the reduced
hepatic blood ﬂow [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 ﬂow being relatively increased,
the Cori cycle (gluconeogenesis) may be insuﬃcient 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
α- and β-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 β-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 ﬂow may reduce the available number of hepatic sinusoids.
Norepinephrine decreases the hepatic blood volume—even the plasma volume in hepatic sinusoids
may be inﬂuenced [81]. Blood ﬂow 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.
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According to the aspects described above, lactate and glucose concentrations in well-trained
endurance athletes gradually decreases during low-intensity exercise. As a large part of gluconeogenesis,
accumulating lactate may be predominantly oxidized during rest or low-intensity exercise in the liver.
However, this may be insuﬃcient to produce appropriate glucose concentrations because of the low
concentration of lactate and in addition the large energy source derived from fat between rest and
low-intensity exercise. Further assumptions and available evidence are discussed in upcoming sections.
5. Allosteric Regulation between Glycolysis and Gluconeogenesis
Allosteric regulation between glycolysis and gluconeogenesis can depend on the release of insulin,
glucagon and cortisol. The role of glucagon and cortisol is to increase the concentration of blood
glucose, while in opposition, insulin decreases blood glucose [83–85].
Hormonal regulation of metabolic reactions in the liver occurs by two major mechanisms. First,
glucagon and β-adrenergic agonists interact with plasma membrane receptors which are associated
with adenylate cyclase. The activity of these membrane-bound receptors increases intracellular cyclic
adenosine monophosphate (cAMP) which drives the activation of cAMP-dependent protein kinase
and catalyzes the phosphorylation of many protein substrates. Finally, these cascading events induce
the activation of gluconeogenesis and inhibit glycolysis [86,87].
Second, those hormones act via alterations in intracellular calcium ion (Ca2+) concentration
levels. Alpha-adrenergic agonists, vasopressin and angiotensin interact with their speciﬁc plasma
membrane receptors to induce two intracellular messengers, myoinositol-1,4,5-trisphosphate and
1,2-diacylglycerol [88]. These increase intracellular Ca2+, which in combination with calmodulin or other
eﬀectors, stimulates a number of Ca2+-associated protein kinases including Ca2+/calmodulin-dependent
protein kinase, phosphorylase kinase and protein kinase C. Furthermore, protein kinase catalyzes
phosphorylation of many protein substrates which lead to alterations in gluconeogenic and glycolytic
ﬂux [86].
Phosphoenolpyruvate is partly recycled to pyruvate (for short-term hormonal regulation), during
gluconeogenesis in perfused liver and isolated hepatocytes [89–92]. This ﬂux is strongly inhibited by
glucagon and cAMP. Liver-pyruvate kinase (PK), an allosteric enzyme, inhibits sigmoidal kinetics
with regard to phosphoenolpyruvate (PEP). This enzyme is allosterically activated by fructose 1,
6-bisphosphate (Fru-1, 6-P2) and repressed by alanine and ATP. The in vitro studies of physiological
concentrations of alanine, ATP and PEP, showed that these enzymes would be inhibited if they are not
activated by Fru-1, 6-P2 [93,94].
From rest through moderate intensity exercise, ATP is primarily generated from fat oxidation [27].
The increased plasma/blood glucose concentration inhibits non-esteriﬁed fatty acid (NEFA) released
by adipose tissue, by secreting insulin. In turn, elevated NEFA can decrease insulin and glucose
concentrations and fatty acids are predominantly released and oxidized [95]. Moreover, Khani et al. [84]
suggested that the infusion of cortisol increased NEFA. Therefore, it is important to recognize that
cortisol increases lipolysis and NEFA concentrations. They also found moderate correlations between
NEFA and gluconeogenesis in diﬀerent observed groups (r = 0.599–0.665). These results do not indicate
cause and inﬂuence. However, associations between NEFA and the rate of gluconeogenesis suggested
existence of a relationship [96–98]. Mitochondrial acetyl-CoA acts as a key allosteric activator of
pyruvate carboxylase (PC) which is activated from increased fatty acid. This allosteric activator leads
to increased production of oxaloacetate for gluconeogenesis oxidation [99].
6. Regulation of AMPK in Energy Metabolism
AMP-activated protein kinase (AMPK) is a key regulator of physiological energy dynamics and
functions by limiting anabolic, while facilitating catabolic pathways. AMPK is a heterotrimer and
possesses an α (α1 and α2)-catalytic subunit and β (β1 and β2) and γ (γ1 and γ2 and γ3)-catalytic
subunits. Three subunit combinations exist in human skeletal muscle. These are α1/β2/γ1, α2/β2/γ1
and α2/β2/γ3 [100]. γ3 is expressed predominantly in glycolytic skeletal muscle while there is very low
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level of γ3 expression in oxidative muscles. The role of α1, α2 and γ3, during contraction of skeletal
muscle or while exercising, in glucose metabolism has been broadly investigated [100,101].
The function of AMPK is to be a sensor in most tissues and organs including liver, skeletal muscle,
heart, hypothalamus and adipose tissue. AMPK works by inﬂuencing enzymatic activities directly
and is involved in biosynthesis of carbohydrates, lipids and proteins. AMPK regulates glucose and
lipid metabolism and activates hepatic AMPK causing increased fatty acid oxidation [102]. AMPK
is activated by a variety of exercise stresses. These typically alter cellular AMP: ATP ratio, either
by increasing ATP or decreasing ATP production due to hypoxia, glucose deprivation or inhibition
of mitochondrial oxidative phosphorylation [103]. There are conﬂicting results related to fatty acid
oxidation induced by exercise. The concentration of AMPK induces fatty acid oxidation by utilizing
an AMPK activator, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR). In common
with exercise, in skeletal muscles, AICAR aﬀects the phosphorylation of acetyl-CoA carboxylase 2
(ACC2) which is an isoform of squamous cell carcinoma (SCC). AICAR increases the rate of uptake of
long-chain fatty acids in cardiac myocytes via translocation of fatty acid translocase (FAT)/CD36 to
the sarcolemma [104]. This mechanism reduces the level of malonyl-CoA and releases the inhibition
of fatty acids uptake into mitochondria via carnitine palmitoyl transferase 1, resulting in fatty acid
oxidation [101,105].
However, α2-AMPK activation is unnecessary for increasing fatty acid oxidation during exercise
of low-intensity [101]. Miura et al. [101] suggested that in skeletal muscle, α2-AMPK may not have
a major role in the shift to fatty acid oxidation from glucose oxidation while fasting, because the
respiratory quotient ratio and utilization of oxygen during the fasting state remained constant between
α1-AMPK -dominant-negative transgenic mice and wild-type littermates. Peripheral lipolysis can be
maximally stimulated at the lowest exercise intensity in humans as well as at 25% of VO2max, whereas
uptake of plasma glucose and oxidation of muscle glycogen increases with exercise intensity [106].
At 30% of VO2max, such as during prolonged low-intensity exercise, free fatty acid oxidation increases
progressively while glucose oxidation is decreased [107]. Nevertheless, the increased activity of
α2-AMPK is not necessary for increases in oxidation of fatty acid in skeletal muscle during endurance
performance [101].
7. Fat Oxidation Stimulates Gluconeogenesis and Can Decrease Glucose in Blood
Low-intensity exercise causes fat oxidation that increases gluconeogenesis which occurs mostly in
the liver and kidney [25,36,108–113]. In both, the liver and kidney, glycerol can be converted directly
to glycerol 3-phosphate by glycerol kinase when glycerol is plentiful. Glycerol 3-phosphate is further
converted to dihydroxyacetone phosphate by glycerol 3-phosphate dehydrogenase for gluconeogenesis.
The direct conversion to glycerol 3-phosphate from free glycerol is believed to be trivial in skeletal
muscle as well as in adipose tissue due to lower activity of glycerol kinase [114–117]. However,
Guo et al. [118] suggested that the capacity for using blood glycerol for intracellular triacylglycerol (TG)
synthesis in skeletal muscle is greater than was seen in previous studies [114–117]. Indeed, glucose
was a constitutive substrate for muscle TG glycerol synthesis which may have provided TG derived
glycerol with carbons [118]. The almost complete loss of 3H label in relation to 14C from blood glucose
in muscle TG glycerol suggests (calculation of 3H label from glucose) that glucose passed through PC
catabolized reactions and thus gluconeogenic precursors may also have paved their way to triglyceride
glycerol [118,119]. Consequently, a pattern of preference to blood glycerol via blood glucose for TG
glycerol synthesis in type 1 ﬁber-rich muscle was observed and its glycerol kinase activity was higher
than in other types of muscle. Blood glycerol for intramuscular synthesis of TG glycerol is associated
with the capacity of muscle to oxidize as well as store fatty acids [115,118].
Fatty acid availability is increased by mobilization of triglycerides in liver and adipose tissue.
Increased fatty acid oxidation induces an increased rate of ketone-body formation and increased tissue
concentrations of acetyl-Coenzyme A (CoA), fatty acyl-CoA and reduced NAD+ [108]. The oxidation
of pyruvate is decreased due to inhibition of pyruvate oxidase by acetyl-CoA or competitive CoA
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between pyruvate oxidase and the fatty acid oxidation system [120,121]. Accordingly, the complex
mechanisms of pyruvate dehydrogenase include inhibition of end products by increases in concentration
of mitochondrial acetyl-CoA, NADH and ATP. These can originate from fatty acid oxidation as
well [122,123]. Pyruvate is converted to acetyl-CoA by pyruvate dehydrogenase (PDH). However,
increased mitochondrial acetyl-CoA from fatty acid ß-oxidation activates pyruvate dehydrogenase
kinases (PDHKs 1–4) and PC, which results in inhibition of PDH [108,124]. This enables the entrance
of acetyl-CoA, derived from fatty acid oxidation in the ﬁrst span of the tricarboxylic acid (TCA) cycle,
to generate citrate. However, employment of the second span of the TCA cycle becomes reliant on
NADH and FADH2 re-oxidation originating from fatty acid ß-oxidation [125].
Fatty acid oxidation can involve increased acetyl-CoA and inhibition of PDH. The TCA cycle must
be substituted to allow continued function (anaplerosis) if its anions are removed. Due to inhibited
PDH, PC is the major anaplerotic enzyme which immediately synthesizes oxaloacetate from pyruvate
in the mitochondria [126]. During stimulated gluconeogenesis, the oxaloacetate concentration can fall
due to increased PC activity. This can be explained by conversion of pyruvate into oxaloacetate that is
still formed to malate. Thus, the metabolic production of the pyruvate carboxylase reaction may be
related to the sum of malate and oxaloacetate [108,127,128]. In many tissues, the activity of PC is high
(e.g., 10 to 12 units per gram in liver) and acetyl-CoA plays a role as a positive allosteric regulator of
the enzyme, respectively [126].
This anaplerotic mechanism is mandatory during gluconeogenesis and lipogenesis when the
reversible reaction from oxaloacetate to malate in the cytosol takes place with the aid of the
malate–aspartate shuttle for gluconeogenesis or citrate for lipogenesis (oxaloacetate to cytosol,
acetyl-CoA, malonyl-CoA) which exists in mitochondria and is still metabolized from glucose or
fatty acids. Therefore, malate, but not oxaloacetate can traverse the inner membrane of mitochondria.
Additionally, formation of malate is promoted by increased delivery of NADH from fatty acid
oxidation [129].
Aspartate is converted to oxaloacetate to recruit cytosolic oxaloacetate by cytosolic aspartate
aminotransferase. Hence, the eﬀect of net redox-reaction of malate–aspartate shuttle is the oxidation of
NADH to NAD+ in cytosol and reduction to NADH in the matrix. Accordingly, malate, aspartate and
citrate are transferred precursors for oxaloacetate to gluconeogenesis [125,126].
It is equally relevant to remove TCA cycle intermediates and to avoid accumulated anions
in the mitochondrial matrix. Cataplerotic reactions relate to disposal of TCA cycle intermediates.
Phosphoenolpyruvate carboxykinase (PEPCK), which highly important in cataplerosis, generates PEP
from oxaloacetate to be utilized for gluconeogenesis in the liver and kidney. Pyruvate is transported
into the mitochondria where it is then converted into oxaloacetate or acetyl-CoA, respectively by
PC and PDH. Mitochondrial oxaloacetate depends largely upon the distribution of PEPCK between
cytosol and mitochondria [130]. The increase in phosphoenolpyruvate concentration is associated with
decreased oxaloacetate concentration which may indicate activation of PEPCK [108,131]. The PEP from
glycolysis otherwise can be converted to pyruvate that is decarboxylated to acetyl-CoA for ensuing
oxidation to carbon dioxide (CO2) in the TCA cycle of muscle [126,132].
From muscle, glutamine can be transported to the kidney where ammonia is formed by utilization
of the amino and amide groups. For generation of ammonia, glutamine goes through anaplerotic
reactions to build α-ketoglutarate which joins the TCA cycle and is consequently metabolized to
malate. Malate is further oxidized in the cytosol to oxaloacetate and to PEP and then to glucose [126].
The gluconeogenic pathway in liver and kidney is as follows: PEP, 2 phosphoglycerate, 3 phosphoglycerate,
1.3-bisphosphoglycerate, glyceraldehyde 3-phosphate (G3P) ↔ dihydroxyacetone phosphate (DHAP),
fructose 1.6-bisphosphate, fructose 6-phosphate, glucose 6-phosphate and glucose [126].
Subsequently, reduced blood glucose concentration at the initial stages of low-intensity exercise
(LT test) may occur because the glucose, through gluconeogenesis, seems to be transported to muscle
cells via blood as an ongoing process and may be used as substrate for muscle TG glycerol synthesis.
However, it is unclear whether this transferred blood glucose enters glycolysis or glycogenesis in
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muscles. The enzyme activity in human is similar to animals like the rat. Earlier studies were conducted
by investigations using isotope tracers and arterial-venous diﬀerence. Although outstanding studies of
gluconeogenesis were developed, phenomena in humans were never investigated because of technical
limitations such as gluconeogenesis from lactate [64]. The factors mentioned above are summarized in
Figure 2.
Figure 2.
Summarized illustration of all described factors for decreased blood glucose and
lactate values during the initial stages of lactate threshold test.
ADP—adenosine diphosphate;
ATP—adenosine triphosphate; ASAT—aspartate transaminase; DHAP—dihydroxyacetone phosphate;
ETC;—electron transport chain; FAD—ﬂavin adenine dinucleotide; F 1;6-B—fructose 1;6-bisphosphate;
F 6-P—fructose 6-phosphate; G3P—glyceraldehyde 3-phasphate; G 6-P—glucose 6-phosphate;
LDH—lactate dehydrogenase;
PDH—pyruvate dehydrogenase;
PEP—phosphoenolpyruvate;
Pi—inorganic phosphate;
MCT—monocarboxylate transporter;
NAD—nicotinamide adenine
dinucleotide; 1;3-BG—1;3-bisphosphoglycerate; 2-PG—2 Phosphoglycerate 3-PG—3 phosphoglycerate.
8. Conclusions
It is already known that fat oxidation is predominantly utilized to perform low-intensity exercise.
This exercise area is crucial for estimating the recovery ability of athletes. During the low-intensity
exercise, the accrued resting lactate may predominantly be transported via blood from muscle cells to
the liver/kidney (ongoing moment) while lactate from muscle cells is less oxidized by the intracellular
lactate shuttle mechanism [45,64]. Furthermore, increased hepatic blood ﬂow according to relatively
more hepatic glucose output than glucose output of skeletal muscle and similar remained hepatic
lactate uptake and lactate output of skeletal muscle during recovery time may support aspects of the
predominant activation of gluconeogenesis (Cori cycle). However, it may be insuﬃcient to induce the
production of needed glucose because of the low concentration of lactate and the large energy source
from fat between rest and low-intensity exercise. Insuﬃcient sympathetic drive also may inﬂuence
blood glucose and lactate concentrations [68,69,133,134].
Fatty acid oxidation activates key enzymes and hormonal responses of gluconeogenesis such as
PK, PC, PEPCK, glucagon, cortisol and other associated regulators such as cAMP and intracellular Ca+,
while glycolysis-related enzyme such as PDH are allosterically inhibited [93,94,99,108,126–128,130–132].
The eﬃcient use of fat oxidation during low-intensity exercise and its eﬀect during LT test
exhibited a rightward shift of the exponential lactate curve. This can be interpreted as improved
Int. J. Environ. Res. Public Health 2020, 17, 5470
10 of 16
regenerative ability, lactate threshold and endurance capacity [2,16–18]. Hence, decreased blood lactate
and glucose may be a signal of eﬃcient utilization of fat oxidation and improved recovery during
low-intensity exercise. In particular, athletes of intermittent sports may need this recovery ability to
improve performance in competition. The eﬃciency of fat oxidation during low-intensity exercise in
athletes may be important to improve the regeneration of exercise performance between and during
competition after highly intensive exercise load. In addition, strength athletes such as weight lifter
may need this recovery ability to optimize the repeated high intensity training session because of the
need for ATP re-synthesis.
Athletes with a relatively poor endurance capability and the general population may show
increased blood glucose concentrations during low-intensity exercise. It indicates that they also use
signiﬁcant amounts of glucose to perform low-intensity exercise. Athletes and the general population
need to low-intensity exercises which activate the corresponding enzymes via fat oxidation resulting
in enhanced endurance and recovery.
Studies and ﬁndings of above-mentioned review were actively investigated and this review can
be a ﬁrst step toward identifying the associations between exercise intensity, blood glucose and lactate
at the low-intensity exercise stages of LT test. Further studies are expected to investigate how these
key enzymes and hormonal responses during low-intensity exercise are actually activated in humans
with regard to gluconeogenesis.
Author Contributions: Conceptualization, W.-H.Y., M.G. and O.H.; methodology, W.-H.Y., H.P., M.G. and O.H.;
writing—original draft preparation, W.-H.Y.; writing—review and editing, W.-H.Y., H.P. and M.G.; visualization,
W.-H.Y. and H.P.; project administration, W.-H.Y. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Acknowledgments: This study was supported by Dong-A University research grant.
Conﬂicts of Interest: The authors declare no conﬂicts of interest.
Abbreviations
AICAR.
Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside
ATP
Adenosine triphosphate
AMPK
Adenosine monophosphate-activated protein kinase
Ca2+
Calcium ions
cAMP
Cyclic adenosine monophosphate
FADH2
Flavin adenine dinucleotide
Fru-1,6-P2
Fructose 1,6-bisphosphate
ICG
Indocyanine green dye
LT
Lactate threshold
mLDH
Mitochondria-localized lactate dehydrogenase
MCT
Monocarboxylate transport
MLSS
Maximal lactate steady state
NADH
Nicotinamide adenine dinucleotide
NEFA
Non-esteriﬁed fatty acid
PDH
Pyruvate dehydrogenase
PC
Pyruvate carboxylase
PEP
Phosphoenolpyruvate
PEPCK
Phosphoenolpyruvate carboxykinase
PK
Pyruvate kinase
SCC
Squamous cell carcinoma
TCA
Tricarboxylic acid
TG
Triacylglycerol
VO2
Oxygen uptake
VO2max
Maximal oxygen uptake
Int. J. Environ. Res. Public Health 2020, 17, 5470
11 of 16
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