Glucose-fructose ingestion and exercise performance: The gastrointestinal tract and beyond

Abstract

Carbohydrate ingestion can improve endurance exercise performance. In the past two decades, research has repeatedly reported the performance benefits of formulations comprising both glucose and fructose (GLUFRU) over those based on glucose (GLU). This has been usually related to additive effects of these two monosaccharides on the gastrointestinal tract whereby intestinal carbohydrate absorption is enhanced and discomfort limited. This is only a partial explanation, since glucose and fructose are also metabolized through different pathways after being absorbed from the gut. In contrast to glucose that is readily used by every body cell type, fructose is specifically targeted to the liver where it is mainly converted into glucose and lactate. The ingestion of GLUFRU may thereby profoundly alter hepatic function ultimately raising both glucose and lactate fluxes. During exercise, this particular profile of circulating carbohydrate may induce a spectrum of effects on muscle metabolism possibly resulting in an improved performance. Compared to GLU alone, GLUFRU ingestion could also induce several non-metabolic effects which are so far largely unexplored. Through its metabolite lactate, fructose may act on central fatigue and/or alter metabolic regulation. Future research could further define the effects of GLUFRU over other exercise modalities and different athletic populations, using several of the hypotheses discussed in this review.

Full text

ORIGINAL ARTICLE
Glucose–fructose ingestion and exercise performance: The
gastrointestinal tract and beyond
ROBIN ROSSET
1
, LÉONIE EGLI
2
, & VIRGILE LECOULTRE
3
1
Department of Physiology, University of Lausanne, Lausanne, Switzerland;
2
Nestle Research Center Singapore, Singapore,
Singapore &
3
Centre for Metabolic Disease, Broye Intercantonal Hospital, Estavayer-le-Lac, Switzerland
Abstract
Carbohydrate ingestion can improve endurance exercise performance. In the past two decades, research has repeatedly
reported the performance benefits of formulations comprising both glucose and fructose (GLUFRU) over those based on
glucose (GLU). This has been usually related to additive effects of these two monosaccharides on the gastrointestinal tract
whereby intestinal carbohydrate absorption is enhanced and discomfort limited. This is only a partial explanation, since
glucose and fructose are also metabolized through different pathways after being absorbed from the gut. In contrast to
glucose that is readily used by every body cell type, fructose is specifically targeted to the liver where it is mainly converted
into glucose and lactate. The ingestion of GLUFRU may thereby profoundly alter hepatic function ultimately raising both
glucose and lactate fluxes. During exercise, this particular profile of circulating carbohydrate may induce a spectrum of
effects on muscle metabolism possibly resulting in an improved performance. Compared to GLU alone, GLUFRU
ingestion could also induce several non-metabolic effects which are so far largely unexplored. Through its metabolite
lactate, fructose may act on central fatigue and/or alter metabolic regulation. Future research could further define the
effects of GLUFRU over other exercise modalities and different athletic populations, using several of the hypotheses
discussed in this review.
Keywords: Endurance, exercise, nutrition, performance, metabolism
Highlights
.Compared to the ingestion of glucose only, ingestion of glucose–fructose mixtures during exercise can improve exercise
performance.
.The benefits of glucose–fructose mixtures are related to fructose specific metabolism.
.Originally thought to occur mainly at the level of the gastrointestinal tract, these benefits extend far beyond the intestine,
and most likely involve the liver and active skeletal muscles.
Abbreviations
GLU glucose ingestion
GLUFRU glucose–fructose ingestion
GLUTs glucose transporter
I:G ratio Insulin:glucagon ratio
SGLT-1 sodium–glucose co-transporter isoform 1
VO
2max
maximal oxygen consumption
1. Introduction
Carbohydrate ingestion can improve prolonged exer-
cise performance. Typical guidelines recommend
ingesting 30–60 g carbohydrate per hour (American
Dietetic et al., 2009). While original recommen-
dations essentially suggested glucose-based formu-
lations (GLU) (Coggan & Coyle, 1991), more
recent guidelines propose that with increased exercise
duration, the optimal intake should not only be
increased (up to 90 g h
−1
carbohydrate during ses-
sions lasting more than 2.5 h), but also that formu-
lations comprising both glucose and fructose
(GLUFRU) may optimize performance (Cermak &
Van Loon, 2013; Jeukendrup, 2014). Combinations
of both monosaccharides have indeed been first
shown to specifically increase performance in 2008
(Currell & Jeukendrup, 2008). In this cross-over con-
trolled study, simulated 40 km cycling time-trial per-
formance was measured after an initial 2 h endurance
bout. Repeated glucose ingestion significantly
© 2017 European College of Sport Science
Correspondence: Robin Rosset, Department of Physiology, Rue du Bugnon 7, CH-1005 Lausanne, Switzerland. E-mail: rosset.robin@
gmail.com
European Journal of Sport Science, 2017
http://dx.doi.org/10.1080/17461391.2017.1317035

enhanced performance by +8% relative to non-
caloric placebo, with a further +8% improvement
observed with a glucose–fructose formulation.
Comparable advantages of GLUFRU over GLU
were repeated in several other works using endurance
cycling or running, in laboratory and in field con-
ditions. In these experiments, improved aerobic exer-
cise capacity and reduced perceived exertion
(Jentjens et al., 2006; Jeukendrup & Moseley, 2010)
were often associated with diminished gastrointesti-
nal complaints (Roberts, Tarpey, Kass, Tarpey, &
Roberts, 2014; Wilson & Ingraham, 2015). Conse-
quently, GLUFRU was particularly recommended
in situations necessitating high carbohydrate inges-
tion rates (>1.2 g min
−1
) (Jeukendrup, 2010),
leading to the promotion of superior formulations
for gastrointestinal function and endurance
performance.
The effects of ingested carbohydrate on exercise
capacity have been traditionally attributed to several
mechanisms, including prevention of hypoglycemia
and direct muscle oxidation, as well as central stimu-
latory effects (Coggan & Coyle, 1991). Yet, contrast-
ing with these general effects of carbohydrate
ingestion during exercise, how GLUFRU further
improve performance remains largely hypothetical.
On their way to provide energy during exercise,
exogenous carbohydrates pass through the gastroin-
testinal tract up to intestinal absorption, then are
directed to the liver by the portal circulation before
being ultimately transferred to working muscles for
oxidation. To complement recent literature reviews
(Cermak & Van Loon, 2013; Jeukendrup, 2014;
Rowlands et al., 2015; Wilson & Ingraham, 2015),
the purpose of the present work is to consider
mechanisms by which GLUFRU could improve per-
formance as compared to GLU, with a specific focus
on processes taking part beyond the gastrointestinal
tract.
2. General background
For decades, there has been a wide recognition that
low muscle glycogen can impair endurance perform-
ance and that endogenous stores can be spared by
carbohydrate ingestion (Coyle, Coggan, Hemmert,
& Ivy, 1986). Either in solid or liquid forms, carbo-
hydrate intake was mainly considered to enhance per-
formance by providing muscle alternative fuels while
diminishing liver and muscle glycogen use (Cermak
& Van Loon, 2013), although this may depend on
the mode or duration of exercise (Stellingwerff
et al., 2007; Tsintzas, Williams, Boobis, & Greenhaff,
1995; Wallis, Dawson, Achten, Webber, & Jeu-
kendrup, 2006). In turn, these metabolic effects led
to a wide interest in determining the conditions
influencing exogenous carbohydrate oxidization,
typically studied by isotopic techniques. Often com-
bined with indirect calorimetry, this method allows
a distinction between endogenous and exogenous
carbohydrate by monitoring label appearance in cir-
culating metabolites and in expired CO
2
(Tappy,
Paquot, Tounian, Schneiter, & Jequier, 1995).
Accordingly, carbohydrate ingested at increasing
rates was shown to appear in a dose-dependent
manner in the systemic circulation and to be accord-
ingly oxidized. However, this effect was also found to
plateau at high ingestion rates that can vary with
different saccharides (Jeukendrup & Jentjens, 2000).
Since the plateaus of glucose or glucose polymers,
oxidation (up to ≈1gmin
−1
) are higher than those
of other monosaccharides (fructose and galactose:
≈0.4 g min
−1
) (Jeukendrup & Jentjens, 2000), mix-
tures of glucose or glucose-based polymers appeared
as the most susceptible carbohydrate to enhance
performance.
The factors dictating the plateau in exogenous
carbohydrate oxidation during exercise remain
unclear. Indirect calorimetry, isotopic labelling of
ingested carbohydrates and monitoring of the appear-
ance of the label in expired CO
2
are usually used in
conjunction to determine total as well as exogenous
carbohydrate oxidation rates. However, even com-
bined, these techniques fall short in identifying oxi-
dation site and which metabolite derived from
labelled carbohydrates are ultimately oxidized
(Tappy et al., 1995). Hence, they provide little infor-
mation on factors limiting exogenous carbohydrate
oxidation during exercise. Theoretically, these limit-
ations could reside anywhere in the gastrointestinal
tract (gastric emptying, digestion and intestinal
absorption) or in metabolic processes (intestinal
metabolism, hepatic first-pass and release into sys-
temic circulation, muscle uptake and oxidation).
One remarkable finding was that exogenous glucose
oxidation is not limited by cardiac output, peripheral
blood flow and muscle metabolism. Indeed, a periph-
eral glucose infusion was found to be oxidized up to
rates (≈2.5 g min
−1
) much higher than the plateau
observed with oral glucose (Hawley, Bosch, Weltan,
Dennis, & Noakes, 1994). Maximal exogenous
glucose oxidation was also considered independent
from gastric emptying (Rehrer et al., 1992). Conse-
quently, the limitation was concluded to be located
either in the gut or in the liver (Jeukendrup & Jent-
jens, 2000).
Digestion of glucose polysaccharides into glucose
could be argued to limit fuel provision during exer-
cise. However, the fact that short-chain glucose poly-
saccharides such as maltose and short-chain
maltodextrins reached similar maximal oxidation
rates as glucose indicated that the factor limiting
2R. Rosset et al.

maximal exogenous glucose oxidation may not be
found within pre-absorptive mechanisms (Jeu-
kendrup & Jentjens, 2000). Consequently, the limit-
ation of carbohydrate oxidation was supposed to
stand at the level of intestinal absorption, with the
≈1gmin
−1
plateau being consistent with jejunum
glucose absorption kinetics. This hypothesis was pri-
marily based on multiple intestinal segmentations
experiments showing limited absorption of concen-
trated glucose solutions (Shi et al., 1995). Another
physiological effect of exercise, decreased splanchnic
blood flow, may also limit intestinal absorption
capacity. Yet, in absence of invasive direct assess-
ments of glucose flows across the intestinal barrier,
the notion that intestinal absorption limits exogenous
glucose oxidation during exercise remains a
hypothesis.
The plateau in exogenous glucose oxidation may
also result from hepatic limitations. Indeed, the
necessary route for ingested carbohydrate is to
follow portal circulation to the liver, where they can
either be stored, metabolized or can pass to the sys-
temic circulation. The liver is also known to play a
pivotal role in euglycaemia maintenance through
releasing the precise amount of glucose required to
match extrahepatic utilization (Moore, Coate,
Winnick, An, & Cherrington, 2012). After meals,
this results in part of carbohydrate intake being
extracted at first-pass while diminishing the amount
appearing in the systemic circulation as well as
hepatic glucose production. Interestingly, the total
systemic glucose appearance allowed by this mechan-
ism (the sum of hepatic glucose production and
carbohydrate intake not extracted at first-pass) is
thought to be autoregulated at a maximal value
close to 1 g min
−1
, with higher gut absorption fluxes
believed to be directed into hepatic glycogen
(Moore et al., 2012). How this contributes to the
observed plateau in exogenous glucose oxidation
remains unknown as of yet. The understanding of
the responsible sites may also be complicated by
entero-hepatic crosstalk via portal signals (Moore
et al., 2012). Hence, the factors responsible for the
limitation in exogenous glucose oxidation during
exercise remain unclear, but probably not restricted
to intestinal glucose absorption.
3. Glucose–fructose formulations
Fructose, of similar chemical formula than glucose,
has always been part of the human diet since our
hunter-gatherer ancestors who consumed fruits, veg-
etables and root crops (Tappy & Le, 2010). Fructose
oxidation during exercise is lower than that of glucose
(Massicotte, Peronnet, Adopo, Brisson, & Hillaire-
Marcel, 1994), and pure fructose has been reported
to cause gastrointestinal symptoms together with
limited intestinal absorption when provided at high
rates during exercise (Fujisawa et al., 1993). Conse-
quently, and despite few results showing equivalent
oxidation to glucose when ingested before exercise
(Decombaz et al., 1985), pure fructose was generally
considered of poor interest for exercise performance
(Jeukendrup & Jentjens, 2000).
In contrast to pure fructose, formulations compris-
ing both monosaccharides (GLUFRU) can induce
interesting effects for endurance performance. This
was first reported in a study showing that a mixture
of 50 g glucose and 50 g fructose was more efficiently
oxidized during exercise than 100 g of pure glucose
or pure fructose (Adopo, Peronnet, Massicotte,
Brisson, & Hillaire-Marcel, 1994). In following
works, very high oxidation of GLUFRU were
reported at high carbohydrate ingestion rates (Jeu-
kendrup, 2014), enabling to exceed the GLU
plateau of 1 g min
−1
to reach a maximal 1.7 g min
−1
(Jentjens, Moseley, Waring, Harding, & Jeukendrup,
2004). The higher oxidation of GLUFRU as com-
pared to GLU alone was no more observed when
carbohydrate ingestion rates were lower (Hulston,
Wallis, & Jeukendrup, 2009), further suggesting
that GLUFRU may overcome the limitation found
with single monosaccharides. Several studies also
suggested that combining roughly twice as much
glucose as fructose led to the highest exogenous
carbohydrate oxidation (Jeukendrup & Moseley,
2010) and this ratio was deemed optimal.
Others tried to further define conditions leading to
superior GLUFRU oxidation by varying saccharides
amounts, and noticed that oxidation was maximal
with glucose:fructose ratios close to 1.0 (providing
as much glucose as fructose) (O’Brien, Stannard,
Clarke, & Rowlands, 2013; Rowlands et al., 2015).
This may not come as a surprise considering
glucose and fructose abundances in natural products.
Indeed, an analysis of saccharides composition,
reporting starch content as glucose, from 30
common edible fruits, vegetables and cereals
(Figure 1) indicates that the median glucose:fructose
ratio is approximatively 1.3 but also that the distri-
bution may be skewed towards higher ratios due to
glucose-abundant starchy food items. Excluding
starches, saccharides present in sugars can be esti-
mated using free glucose, free fructose and sucrose,
considered to act similarly as 1 glucose and 1 fructose
monomers (Wallis & Wittekind, 2013). Interestingly,
this leads to a median glucose:fructose of 1.0,
suggesting that the optimal effects of GLUFRU
during exercise may actually mirror the ratios
between both monosaccharides in natural foods that
were frequently consumed by our hunter-gatherers’
ancestors.
Glucose–fructose ingestion and exercise performance 3

4. Effects of GLUFRU in the
gastrointestinal tract
GLUFRU ingestion has been classically associated
with gastrointestinal benefits compared to pure
glucose or fructose (Rowlands et al., 2015). Exper-
iments using hydrogen breath testing indeed
showed that fructose malabsorption can be prevented
when co-ingested with similar amounts of glucose
(Latulippe & Skoog, 2011). Others indicated symp-
toms of gastrointestinal discomfort to be lower with
GLUFRU feedings during exercise as compared to
GLU (Jentjens et al., 2006). This can indeed limit
exercise performance, and require exploring why
the co-ingestion of glucose and fructose may limit
these detrimental symptoms.
Fructose may accelerate pre-absorptive carbo-
hydrate delivery. This is illustrated by a faster gastric
emptying with fructose and sucrose than glucose,
both at rest (Sole & Noakes, 1989) and during exercise
(Jeukendrup & Moseley, 2010). This is likely second-
ary to a more rapid intestinal absorption and thus to a
decreased feedback inhibition to the stomach (Weber
& Ehrlein, 1998). A few days of fructose exposure
were also shown to increase subsequent gastric empty-
ing of fructose-containing solutions (Yau, McLaugh-
lin, Maughan, Gilmore, & Evans, 2014), while
dietary fructose is also considered to mediate
sucrase-isomaltase expression (Rosensweig &
Herman, 1968). Thus, fructose consumption seems
to favour carbohydrate delivery to the intestinal
mucosa both acutely and chronically. To what extent
these mechanisms explain the superior uptake and oxi-
dation of GLUFRU over that of GLU remains
unclear, similarly as if this could be used to train the
gastrointestinal tract to improve carbohydrate absorp-
tion during exercise.
Glucose and fructose co-ingestion may increase
total carbohydrate intestinal absorption. This hypoth-
esis (Shi et al., 1995) was based on luminal fructose
and glucose absorption occurring through different
main transporters (GLUT5 vs. SGLT1). Combining
glucose and fructose was then proposed to increase
carbohydrate absorption, provided SGLT1 becomes
saturated at a given glucose ingestion rate. Accord-
ingly, total carbohydrate absorption was found to be
higher with GLUFRU than GLU in proximal sec-
tions of the jejunum (Shi et al., 1995), leading to a
‘multiple transportable carbohydrate’model
whereby improved gut carbohydrate absorption
leads to overall increased flux to working muscle
(Jeukendrup, 2010).
Despite of the preceding, the improved intestinal
function with GLUFRU may also result from other
mechanisms. Regulation of glucose and fructose
absorptions actually occurs through additional trans-
port proteins (GLUT2, GLUT8-12) in close inter-
action with GLUT5, SGLT1 and ion channels
(Chen, Tuo, & Dong, 2016). GLUT2 was proposed
to be particularly key through its translocations both
at the apical and basolateral sides of enterocytes
(Rowlands et al., 2015) but exact fluxes through
each of these transport systems remain unclear. Fruc-
tose is also well documented to be partly metabolized
in enterocytes (Tappy & Le, 2010), possibly affecting
local homeostasis. Consequently, how carbohydrate
absorption fluxes are dictated by apical transport,
intraenterocellular metabolism and basolateral trans-
port is so far unknown. The difference between
Figure 1. Glucose:fructose ratio in 30 selected fruits, vegetables and cereals. Data originate from United States Department of Agriculture
national nutrient database (Retrieved 21 September, 2016, from https://ndb.nal.usda.gov). Only raw products and single varieties per
species are included. The glucose:fructose ratio is typically very high in foods such as cereals or tubercles. The predominant energy
storage form for vegetal organisms, starches, can indeed contain hundreds to thousands of glucose molecules. In contrast, when the
edible part corresponds to leafs, stems or fruits (highlighted in black), the absorbable glucose:fructose ratio is much closer to identity.
4R. Rosset et al.

GLUFRU and GLU is thus most likely partly
explained by additive effects of glucose and fructose
in the gastrointestinal tract, effects that remain to be
outlined. Interestingly, there is also evidence of
important roles played by the combination of both
monosaccharides in organs such as the liver.
5. Effects of fructose and GLUFRU on
hepatic metabolism
Distinct effects of exogenous carbohydrate are also to
be found in post-absorptive, metabolic processes. In a
1994 study, constant amounts of glucose or fructose
(0.8 g min
−1
) were provided to subjects displaying a
wide range of aerobic capacity (Massicotte et al.,
1994). Both exogenous glucose and fructose oxi-
dation were directly related to each subject metabolic
rate, respectively contributing to 14% and 9% of
energy expenditure, as would not be predicted
solely by intestinal absorption saturation. Rather,
this suggests that glucose and fructose oxidation,
and thus their respective delivery into the systemic
circulation, are also regulated by post-absorptive
metabolism.
Unlike glucose, which is directly used by all body
cells, fructose is characterized by a specific, two-
step metabolism (Mayes, 1993; Tappy & Le, 2010)
in which it is first metabolized in splanchnic organs
(particularly the liver), then released as secondary
substrates for other organs (Mayes, 1993; Tappy &
Le, 2010). First-pass splanchnic fructose extraction
is almost complete (>90%, much greater than the
≈33% glucose extraction) (Tappy & Le, 2010),
resulting in oral loads eliciting only small (0.3–
0.4 mmol L
−1
), transient increases in systemic fruc-
tose concentrations (Rosset et al., 2017). This is
also unlikely to be markedly altered during exercise
with fructose following the oral route. In one very
specific experiment in which splanchnic first-pass
was bypassed by using a systemic fructose infusion,
45% fructose was still found to be extracted by
splanchnic tissues as measured by arteriovenous
difference, with exercising and resting muscles
being both responsible for 28% fructose extraction
(Ahlborg & Bjorkman, 1990). However, these were
supraphysiological conditions in which systemic fruc-
tose concentrations (4.8 mmol L
−1
) could compete
for the access to muscle hexokinases, which normally
privilege glucose substrate because of a much higher
affinity than for fructose, K
m
: glucose ≈4×10
−5
vs.
fructose: ≈3×10
−3
mmol L
−1
(Tappy & Le, 2010).
Accordingly, the authors considered that the
amount of oral fructose directly metabolized in
muscle is minimal during exercise, but that fructose
is rather first metabolized into second-hand
metabolites later used as energy substrates by
working muscles (Ahlborg & Bjorkman, 1990).
Fructose splanchnic metabolism can be explained
by the expression of a unique set of enzymes directing
fructose carbons into a specific, efficient pathway
called fructolysis (Figure 2) (Tappy & Le, 2010).
After intracellular entry, fructose is rapidly phos-
phorylated by fructokinase (K
m
≈0.1 mmol L
−1
)
(Tappy & Le, 2010) into fructose-1-phosphate,
then cleaved by aldolase B and phosphorylated by
triokinases into trioses-phosphate. Importantly, fruc-
tokinase displays a higher activity than aldolase B,
leading to transiently increased fructose-1-phosphate
concentrations during active fructolysis. The sub-
sequent disposal of trioses-phosphate can be variable,
and isotopic studies (Sun & Empie, 2012) showed a
Figure 2. In splanchnic organs, fructolysis generates trioses-P with
a build-up of fructose-1-P. Fructose entry occurs through several
transporters of the GLUT family (mainly GLUT2, GLUT5).
Thereafter, fructose is metabolized through a set of three reactions
called fructolysis. Fructolysis begins with the initial phosphoryl-
ation of fructose into fructose-1-P by fructokinase. The enzyme
responsible for the subsequent step, aldolase B, cleaves fructose-
1-P into two three-carbon molecules, dihydroxyacetone-phosphate
(DHAP) and glyceraldehyde, later phosphorylated by triokinases to
glyceraldehyde-3-P. The two trioses-phosphate Glyceraldehyde-3-
P and DHAP are also intermediates of glucose metabolism, and
can therefore be directed to several fates. Of note, since the activity
of fructokinase is higher than that of aldolase B, active fructolysis
results in a rapid build-up of fructose-1-P in fructose-metabolizing
splanchnic cells. Symbols: GLUTs: glucose transporters; P: phos-
phate; Glycer: glyceraldehyde; DHAP: dihydroxyacetone-
phosphate.
Glucose–fructose ingestion and exercise performance 5

large part of a pure fructose load to be converted into
glucose (29–54%) and lactate (25–30%) then
released into the circulation. Compared to dietary
glucose, fructose is known to increase plasma
glucose and insulin concentrations to a lower
extent, but to induce a sustained increase in plasma
lactate concentrations (Decombaz et al., 1985;
Rosset et al., 2017). Fructose-containing carbo-
hydrate formulations are also generally reported for
their ability to replenish liver glycogen during post-
exercise recovery (Décombaz et al., 2011; Gonzalez,
Fuchs, Betts, & van Loon, 2016), with a very small
proportion of fructose carbons converted into lipids
(Sun & Empie, 2012). During exercise, net fructose
storage is decreased while fructose oxidation is
increased (Egli et al., 2016), however. An under-
standing of the benefits of GLUFRU over GLU
may then require a comparative description of
hepatic function during exercise in several nutritional
conditions.
The normal action of the liver is to simultaneously
consume and produce glucose, with production path-
ways being quantitatively dominant under fasting
conditions (net glucose production). Hepatic
glucose production is a complex process deriving
from the activation of glycogenolysis and gluconeo-
genesis (Moore et al., 2012). Both insulin and
glucagon (and thus the insulin:glucagon ratio, I:G)
control the main regulatory steps of glucose metab-
olism, so that both glycogenolysis and gluconeogen-
esis are responsive to glucose concentrations and
active in the post-absorptive state. During exercise,
net hepatic glucose production is typically increased
by changes in the hormonal milieu (rise in catechol-
amines and drop in the I:G ratio) and in nervous
system activity (Moore et al., 2012). Concentrations
of metabolic precursors also play a role, with glyco-
genolysis and gluconeogenesis being respectively
enhanced by high glycogen and high availability of
substrates such as lactate, glycerol or gluconeogenic
amino acids. Lactate is then also consumed and pro-
duced, with a net consumption during prolonged
exercise (Wasserman, Connolly, & Pagliassotti,
1991). Hence, when exercising in unfed conditions,
the liver sustains glucose production partly via
lactate consumption (net hepatic lactate production
<0) (Figure 3(A)).
Glucose ingestion decreases hepatic glucose pro-
duction. Indeed, the main consequence of glucose
ingestion is to increase plasma insulin which,
through elevating I:G ratio, promotes hepatic
glucose disposal. By stimulating glycolysis, this also
causes an accumulation of fructose-1,6-biphosphate,
which represents an important co-activator
Figure 3. Models of hepatic carbohydrate metabolism during exercise. Exercise typically increases circulating catecholamines and glucagon
and decreases insulin concentrations. When unfed (A), this increases Glucose-6-P concentrations through driving glycogen breakdown and
gluconeogenesis from three-carbon precursors such as lactate. High Glucose-6-P and low insulin:glucagon ratio then favour glucose pro-
duction and systemic release. Hence, the liver sustains plasma glucose concentrations and acts as a net glucose producer partly through
net lactate uptake (i.e. net lactate production <0) as part of the Cori Cycle. Through increasing insulin and I:G ratio, glucose ingestion
during exercise (B) slows glycogenolysis and gluconeogenesis and thus limits Glucose-6-P concentrations. Part of Glucose-6-P can then
be directed into lower glycolysis to pyruvate and lactate, with Fru-1,6-biP acting as a co-activator via feed-forward mechanisms. Therefore,
glucose ingestion during exercise can partially or totally preserve hepatic carbohydrate metabolism (i.e. both net fluxes ≈0). Co-ingested with
glucose (C), fructose affects hepatic metabolism by mass effects of its carbons and via allosteric mechanisms. Active fructolysis leads to build-
up of Fru-1-P, Trioses-P and Fructose-1,6-biP. Fru-1- P then activates lower glycolysis to pyruvate which, together with Fru-1,6-biP, drives
part of fructose carbons into lactate. Fructose carbons can also undergo gluconeogenesis and replenish Glucose-6-P concentrations. Fru-1-P
actions to favour hepatic glucose entry and glycogen storage are in balance with the hormonal milieu during exercise. Ingesting glucose and
fructose can thus result in both net glucose and lactate productions (i.e. ‘reverse Cori cycle’) to alter hepatic function as a carbohydrate buffer
during exercise. Symbols: Fru: fructose; P: phosphate; I:G ratio: insulin:glucagon ratio.
6R. Rosset et al.

channelling trioses-phosphate into lactate (Mayes,
1993). Compared to unfed exercise, the overall effect
of glucose ingestion during exercise thus favours oppo-
site pathways, glucose consumption and lactate pro-
duction, and the liver can be viewed as a buffering
organ for carbohydrate metabolism (net glucose and
lactate productions ≈0) (Figure 3(B)).
Compared to fasted and glucose-fed exercise, fruc-
tose markedly and complexly affects hepatic metab-
olism. The mass effects of fructose carbons were
specifically visible in 1996 (Paquot et al., 1996). In
this work, fructose increased hepatic glucose pro-
duction by 20% only when provided with simul-
taneous physiologic hyperglucagonemia (low I:G
ratio), indicating that fructose carbons can be
diverted to various fates depending on the hormonal
milieu. In addition to these mass effects, fructose was
also shown, through its intermediate fructose-1-
phosphate, to allosterically favour hepatic glucose
uptake and storage into glycogen and pyruvate pro-
duction (Mayes, 1993; Tappy & Le, 2010). Interest-
ingly, glycogen metabolism is also influenced by
other actions of fructose and by actual glycogen
content (Mayes, 1993; Tappy & Le, 2010), resulting
in a complex interplay of opposed effects. This may
explain why fructose stimulates both glucose and gly-
cogen (assimilated to diphosphoglucose kinetics)
turnovers (Dirlewanger, Schneiter, Jequier, &
Tappy, 2000; Tounian, Schneiter, Henry, Jequier,
& Tappy, 1994). Whether rapid glucose and/or glyco-
gen turnover could affect substrate availability when
metabolic rate is increased during exercise is
unknown (Gonzalez et al., 2016). Contrasting with
glucose ingestion alone, glucose–fructose ingestion
during exercise therefore results in a simultaneous
stimulation of hepatic glucose and lactate pro-
ductions (Figure 3(C)).
The provision of GLUFRU may induce a unique
hepatic physiological response. Indeed, a study
under highly controlled conditions found that the
effect of hyperglycemia/hyperinsulinemia to suppress
hepatic glucose production was partly blunted by
fructose (Dirlewanger et al., 2000), implying that
fructose elevates the point at which the liver switches
from net glucose production to net glucose consump-
tion. Interestingly, a study in rats found also that
glucose co-ingestion exacerbated the effects of fruc-
tose to increase net hepatic lactate production
(Underwood & Newsholme, 1965). Whether these
specific effects also occur during exercise remain
unsettled. However, it may be proposed that
glucose and fructose co-ingestion induce a specific
form of synergy in which fructose decreases the role
of the liver to act as a carbohydrate buffer and in
which glucose increases fructose metabolism into
lactate, respectively. Similar effects were reported in
a 2010 study, in which a glucose:fructose ratio of
1.5 was ingested at a rate of 2.0 g min
−1
during pro-
longed exercise at ≈60% VO
2max
. Compared to an
equimolar GLU condition, GLUFRU resulted in
systemic glucose and lactate fluxes being increased
by respectively ≈10% and ≈30% (Lecoultre et al.,
2010), demonstrating that GLUFRU increase circu-
lating carbohydrate availability compared to GLU.
The relative importance of intestinal and hepatic
processes contributing to the effects of GLUFRU
on exercise performance remains largely unknown.
As with GLU, the site limiting GLUFRU oxidation
cannot be elucidated without invasive portal assess-
ments. Yet, if the difference in maximal oxidation
between GLU and GLUFRU (≈1.2 vs.
≈1.7 g min
−1
) (Jentjens et al., 2004) was entirely
explained for by an improved intestinal absorption,
GLU would rapidly yield to carbohydrate accumu-
lation within the gastrointestinal tract. Considering
that severe gastrointestinal complaints were observed
with as little as 10 g carbohydrate malabsorption
(Rumessen, Hamberg, & Gudmand-Hoyer, 1990),
a similar difference between GLU and GLUFRU
would have been inevitably observed within a
period of 20 min. The fact that GLU indeed fre-
quently induced more gastrointestinal distress than
GLUFRU, but during typically longer exercise
bouts, suggests that intestinal malabsorption was
low and likely not solely responsible for the oxidation
difference between formulations. Instead, this may
further point the importance of the effects of fructose
on hepatic metabolism. Interestingly, a study having
distinctly labelled both glucose and fructose (Row-
lands, Thorburn, Thorp, Broadbent, & Shi, 2008)
revealed that total exogenous carbohydrate oxidation
was maximal along with an optimal oxidation of fruc-
tose, but not of glucose (Rowlands et al., 2015). This
may advocate for a specific role of the intermediary
metabolite lactate.
6. Effects of GLUFRU through lactate
metabolism
Lactate is no longer considered a deleterious waste
product, but rather viewed as a carbohydrate sub-
strate shuttled between and possibly within cells or
organs (Brooks, 2009). These exchanges are influ-
enced by multiple factors, with a critical role of
lactate gradients between plasma/interstitium and
cellular compartments (Van Hall, 2010). Depending
on conditions, skeletal muscle can revert from net
lactate production into net consumption. Interest-
ingly, this can arise from liver damage (Record,
Chase, Williams, & Appleton, 1981), indicating a
critical role of hepatic lactate exchanges. Accord-
ingly, lactate fluxes measured during exercise by
Glucose–fructose ingestion and exercise performance 7

arteriovenous difference (Ahlborg & Bjorkman,
1990) indicated that fructose infusion caused a net
splanchnic lactate production together with net
muscle consumption. This interorgan lactate shuttle
may be either pushed by fructose metabolism increas-
ing splanchnic blood lactate gradient, or pulled by
muscle work increasing blood-muscle lactate
gradient.
How lactate provision may affect muscle fuel selec-
tion remains largely hypothetical. Lactate is known to
be extensively oxidized during exercise and, as com-
pared to glucose, it offers a more immediate conver-
sion into pyruvate while being transported through
separate transport systems. A few experiments
having infused lactate during exercise noticed that it
largely increased lactate oxidation, but however
caused a ≈40% decrease in glucose oxidation and
did not affect muscle glycogen use (Miller, Fattor,
Jacobs, Horning, Navazio, et al., 2002; Miller,
Fattor, Jacobs, Horning, Suh, et al., 2002). Interest-
ingly, similar studies at rest indicated that lactate
infusion also diminished glucose oxidation in hyper-
insulinemia, but only by ≈20% (Paquot et al.,
1995) and that lactate infusion was associated with
a strong thermogenic effect (Ferrannini et al.,
1993). Consequently, if GLUFRU ingestion during
exercise also leads to an increased lactate oxidation
while incompletely suppressing glucose oxidation,
the simultaneous uptake of two different circulating
carbohydrate could allow for an increased maximal
carbohydrate oxidation.
A recent work having measured glycogen depletion
during exercise indicated that both the ingestion of
GLUFRU (as sucrose) or GLU during exercise pre-
served liver glycogen without affecting muscle glyco-
gen use, but that net carbohydrate oxidation was
higher with GLUFRU than GLU (Gonzalez et al.,
2015). This confirmed other observations of
GLUFRU leading to higher carbohydrate oxidation
(Roberts et al., 2014) together with increased lactate
fluxes (Lecoultre et al., 2010)ascomparedtoGLU.
Interestingly, all these works included well-trained
endurance athletes. Recent findings show a higher
direct lactate oxidation in trained than untrained indi-
viduals, the latter relying more on gluconeogenesis to
oxidize lactate (Emhoff et al., 2013). This, in turn,
raises the hypothesis that GLUFRU may differently
affect athletes depending upon their oxidative poten-
tial, with athletes exhibiting a high aerobic capacity
benefiting more from GLUFRU mixtures than
untrained individuals. Interindividual variability in
oxidative capacity can be however high, and how this
may translate into individualized nutritional rec-
ommendations is left to be established.
Figure 4. Compared to glucose-based formulations, the simultaneous ingestion of glucose–fructose results in a higher exogenous carbo-
hydrate oxidation. This could be caused by (1) additive effects in the gastrointestinal tract (gut absorption), leading to higher substrate
fluxes in the portal circulation, (2) a specific hepatic synergy, in which fructose may limit first-pass glucose extraction, while glucose
would increase fructose metabolism into lactate to increase carbohydrate fluxes reaching the systemic circulation (i.e. affecting liver function
as a carbohydrate buffer) and (3) the circulation of dietary carbohydrate as both glucose and lactate may affect muscle fuel selection. Symbols:
CO
2
: carbon dioxide.
8R. Rosset et al.

The effect of GLUFRU may also vary with exercise
modalities. Indeed, most reports of improved exer-
cise performance with GLUFRU over GLU were
obtained during exercise at constant or near-constant
load, with few experiments involving bursts of high-
intensity exercise susceptible to alter lactate metab-
olism (Triplett, Doyle, Rupp, & Benardot, 2010).
Consequently, it remains unclear if the benefits
from elevated lactate oxidation are also to be found
when lactate fluxes are less stable.
Fructose conversion into glucose and lactate will also
likely raise splanchnic metabolic rate, and how this can
contribute to the higher oxidation of GLUFRU than
GLU is unknown (Tappy, Egli, Lecoultre, & Schnei-
der, 2013). During endurance-type exercise, we thus
postulate the observed oxidation profiles to be a
complex consequence of processes taking part in the
gastrointestinal tract, in the liver and also in muscle
(Figure 4). How all processes coordinate to explain
the higher exogenous carbohydrate oxidation observed
with GLUFRU than GLU remains largely unknown,
giving room for further research.
7. Other effects of GLUFRU
Partly replacing glucose by fructose may also have
important non-metabolic consequences. Fructose
generates a different gluco-incretins profile (Tappy
& Le, 2010) and induces different patterns of brain
activation (Page et al., 2013) than glucose. Lactate
itself may be viewed as a ‘lacthormone’acting on
metabolic regulation through binding to a specific
receptor (Philp, Macdonald, & Watt, 2005). In the
brain, this was associated to the neuroprotective
and neurostimulatory effects of exercise (Proia, Di
Liegro, Schiera, Fricano, & Di Liegro, 2016).
Whether glucose combined to fructose and its metab-
olite lactate may modulate the central component of
fatigue was little studied, however. Similarly, lactate
was recently considered responsible for some of the
adaptations to exercise-training (Proia et al., 2016).
How GLUFRU ingestion may contribute to this
process remains to be determined, yet.
8. Conclusion
There is accumulating evidence that GLUFRU can
increase exercise performance more than GLU inges-
tion during prolonged exercise. The proposed mech-
anisms have been largely based on the knowledge of
the effects of GLU-based formulations in the gastroin-
testinal tract. However, glucose and fructose are not
only differently sensed, emptied from the stomach
and absorbed, but are also differently metabolized.
GLUFRU bear the interesting property to distribute
carbohydrate energy as both circulating glucose and
lactate, providing working muscles with a dual source
of carbohydrate. How this modulates muscle fuel selec-
tion and interacts with other, non-metabolic effects of
fructose and lactate is largely unknown. The similarity
between optimal ratios and natural sugars suggest that
ingesting glucose with fructose during exercise may
mirror human evolutionary adaptation.
Acknowledgements
The authors would like to express their profound
gratitude to Prof. Luc Tappy for his helpful com-
ments during manuscript preparation. RR is also
grateful to the European College of Sport Science
for this invitation.
Disclosure statement
The authors report no conflict of interest. LE is an employee of
Nestec SA.
Funding
This project was funded by a research grant to Prof. Luc Tappy
from Swiss National Science Foundation, Bern, Switzerland
(grant nos 32003B-156167 and 320030-138428).
ORCID
Robin Rosset http://orcid.org/0000-0003-4708-2771
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