Update article

Metabolic training: new paradigms of exercise training for metabolic

diseases with exercise calorimetry targeting individuals
J.-F. Brun
a,b,
*
, E. Jean
a,b
, E. Ghanassia
a,b
, S. Flavier
a,b
, J. Mercier
a,b
a
Inserm ERI 25 Muscle et Pathologies , laboratoire de physiologie des interactions, UFR de mdecine, institut de biologie de Montpellier,
universit Montpellier-I, boulevard Henri-IV, 34062 Montpellier, France
b
Service central de physiologie clinique, unit dexploration mtabolique (Ceramm), hpital Lapeyronie, 34295 Montpellier cedex 05, France
Received 2 March 2007; accepted 5 April 2007
Abstract
For patients with metabolic diseases, as with other diseases, exercise training is a fully recognized therapy. Such training helps obese patients
stabilize weight after slimming. For patients with type 2 diabetics, it is both a prevention and a glucose-lowering treatment and reduces health
care costs. We propose a targeted training for individuals at the level of maximal lipid oxidation (LIPOX
max
) with a protocol of exercise calori-
metry (four 6-min workloads) based on Brooks and Merciers crossover concept. Calorimetric interpretation of gas exchange at the fifth and sixth
minutes of each stage shows a bell-shaped curve for lipid oxidation that peaks at LIPOX
max
, a point that varies considerably among individuals.
As well, glucose oxidation is a linear function of power (carbohydrate cost of the watt). Such a calculation predicts fairly actual lipid oxidation
over 45 min at the same level. Other protocols, with 3-min workloads used in sports medicine, are not reliable for patients with metabolic
diseases. For obese adults and teenagers, as well as those with type 2 diabetes, 2 months training at the LIPOX
max
(three sessions at 45 min
per week) results in a net loss of fat mass, with preserved fat-free mass, and increased ability to oxidize lipids. At the end of this period, training
can be re-targeted to be more effective and, possibly, associated with other strategies with stronger exercise intensities. Therefore, metabolic
training is a viable option for patients with metabolic diseases, but the full concept is still evolving. However, the major challenge remains to
transform inactive individuals into active ones.
2007 Elsevier Masson SAS. All rights reserved.
Keywords: Obesity; Diabetes; Exercise; LIPOX
max
; Training; Lipid oxidation
1. Introduction
Recently, exercise was shown to have therapeutic effective-
ness for preventing the onset of type 2 diabetes [25], improving
blood glucose control [33], and preventing further weight
regain in weight-reduced obese individuals [4]. This evidence
led to the consideration of physical exercise as a viable treat-
ment, in endocrinology as in other areas of medicine. This tar-
geting of exercise is now common for respiratory and heart
chronic diseases [32] but not for metabolic diseases. The
usual recommendations for exercise for patients with diabetes
[16] do not take into account the physiological mechanisms
that underlie training effectiveness [28]. Authors indicate only
a range of heart rates supposed to be the most accurate. How-
ever, depending on exercise intensity and duration, muscular
activity promotes carbohydrate or lipid oxidation [27].
Our group believes that with exercise, the preferential tar-
geting of carbohydrate or lipid oxidation does not have the
same therapeutic effects and that targeting based on the indivi-
dualized determination of the maximal level of oxidation of
lipids would improve the effectiveness of training [28]. For
this purpose, we developed a specific test of exercise calorime-
try suitable for practice. This test allows for measuring carbo-
hydrates and lipids at various levels of physical activity [27].
The test may constitute a simple means of evaluating muscular
metabolic alterations and their consequences on the use of
http://france.elsevier.com/direct/ANNRMP/
Annales de radaptation et de mdecine physique 50 (2007) 528534
*
Corresponding author.
E-mail address: j-brun@chu-montpellier.fr (J.-F. Brun).
0168-6054/$ - see front matter 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.annrmp.2007.04.008
energy substrates during exercise for use in guiding individua-
lized metabolic training.
2. Muscular function in the pathophysiology of disease
related to a sedentary lifestyle
2.1. Obesity and muscle
Obesity, which has reached epidemic proportions at the
beginning of the 20th century in Europe and worldwide, is
characterized by excess storage of fat resulting from energy
imbalance: food intake exceeding energy needs. The increasing
sedentary lifestyle of people is one of the main explanations for
this true pandemic. The daily duration of sedentary activities
(min per day) and fat mass are highly related. Being over-
weight appears to be proportional to time spent watching TV,
a duration of 3 daily hours being the threshold beyond which
the risk becomes strong [4].
The muscle of obese patients exhibits metabolic character-
istics [4]. In particular, the balance of substrates used for oxi-
dation during exercise is modified, with alteration in the mus-
cular processing of fats and carbohydrates. A comparison of
the rates of lipid and carbohydrate oxidation at various inten-
sities of exercise in overweight versus standard-weight subjects
shows that sedentary obese subjects have a lower ability to
oxidize lipids as compared with matched controls under the
same relative exercise intensity [27]. Patients with type 2 dia-
betes show a similar profile [17].
2.2. Exercise in obese patients
Abundant literature shows the benefit of endurance exercise
training for obese patients [4]. Obesity is potentiated by seden-
tarism and is prevented by regular activity; exercise, particu-
larly intense exercise, can contribute to weight reduction [4,
5]. As well, exercise is an effective means for obese patients
to stabilizing weight after slimming, thus contributing to main-
taining long-term weight reduction obtained by diet [4,37].
Regular exercise thus contributes to counteracting resistance
to weight loss that appears after each pound lost, in particular
after the most restrictive pounds lost, and results in an almost
inescapable relapse of post-obese patients back to obesity
[37]. In addition, exercise corrects postprandial hyperlipidemia
and thus prevents the anti-insulin effects of high fat diets
[23].
2.3. Type 2 diabetes
For patients with type 2 diabetes, obesity is a both a causa-
tive and a worsening factor in the disease, so the previously
mentioned indications are applicable. Just like obese indivi-
duals, type 2 diabetic individuals have lower ability to oxidize
fat during exercise [17]. However, losing weight is more diffi-
cult in obese diabetic patients than obese nondiabetic patients,
probably because of the effect of antidiabetic drugs and endo-
crine abnormalities, including reduced catecholamine postpran-
dial peak involved in meal-induced thermogenesis.
Exercise has three major benefits in type 2 diabetes. First, it
has a preventive effect on the appearance of the disease [25].
As well, it has a moderate but measurable beneficial effect on
blood glucose control, as evidenced by results of a recent meta-
analysis showing decreased glycated hemoglobin by 0.8%, on
average, after exercise [33]. The results seem minimal, but a
1% decrease in glycated hemoglobin level translates to a 21%
reduction of complications related to diabetes [34]. Finally, tar-
geted exercise training over 1 year reduces by 50% diabetes-
related health care costs [10].
3. Methods of exercise prescription
3.1. Usual recommendations
Unquestionably, physical activity should be promoted in the
management of obesity [4] and diabetes [25]. Training para-
digms, however, could be perfected. Current recommendations
have been summarized by the American College of Sports
Medicine [19].
3.1.1. Duration
The duration of training sessions are generally agreed to be
at least 3045 min, without interruption, since steady state
exercise is a condition for oxidizing a large quantity of lipids;
most leisure activities based on short or intermittent intense
exercises burn carbohydrates.
3.1.2. Frequency
The effects of exercise sessions are quickly reversible [36].
After exercise is stopped, within a few weeks, the metabolic
benefits are rapidly lost, with weight regain [39]. A weekly
session is thus metabolically insufficient, and several sessions
per week appear to be mandatory. The current recommendation
is to perform three sessions per week [19]. Obviously, perform-
ing more is not forbidden.
3.1.3. Intensity
Intensity of exercise appears to be a less standardized issue.
Various levels of intensity have been proposed: 40% [38], 70%
[22], or even 85% of VO
2max
[30]. Such proposals seem arbi-
trary or based on theoretical concepts.
3.2. Our concept: targeting individuals with exercise
calorimetry
We aimed to target training for individuals on the basis of a
measurement, during an exercise test, of the level of exercise at
which oxidation of lipids is maximal [27].
J.-F. Brun et al. / Annales de radaptation et de mdecine physique 50 (2007) 528534 529
3.2.1. Pathophysiological basis for targeted training
in obesity
The rationale for our proposal is that exercise increases fat
oxidation and uses lipids as the major source of energy when
the exercise is prolonged. This increased use of lipids explains,
to a large extent, the increase in the total quantity of energy
used. Thus, a relative sparing of carbohydrates (glycogen
stores) is obtained.
Brooks and Mercier [8,9] proposed a model of these inter-
actions, the crossover concept (Fig. 1). The basis of the con-
cept is the following: 1) lipids constitute the major source of
energy (approximately 60%) for muscle at rest; 2) endurance
training induces biochemical alterations in muscle and endo-
crine adaptations aiming at glycogen sparing, with an adapta-
tion of the flow of glycolysis to fit closely to that of the Krebs
cycle, and an increase in lipid oxidation at low power intensi-
ties; 3) the adjustment of the flow of glycolysis to that of the
Krebs cycle decreases the production of lactate by reducing the
accumulation of pyruvate that enters the Krebs cycle; and 4)
energy needs are determined by the intensity of exercise and
are the main determining factor of the respective proportion of
carbohydrates and lipids used by muscles: use of carbohydrates
becomes predominant at high-intensity. When carbohydrates
represent more than 70% of energy, blood lactate level
increases, and the ventilatory threshold is reached. In general,
these three phenomena occur at the same level. In humans,
endurance training increases the ability to oxidize lipids by
increasing the muscular mitochondrial mass and the enzymes
of -oxidation [8,9].
3.2.2. Procedure for exercise calorimetry
We propose a diagnostic test comprising four or five 6-min
workloads that may be followed by a series of quick increases
in power intensity until the tolerable maximum under these
conditions is reached. The test is performed on an ergometric
bicycle connected to an analyzer, which allows for analyzing
the gaseous exchange cycles by cycling. Electrocardiographic
monitoring and measurements of VO
2
, VCO
2
, and respiratory
exchange ratio (RER) are performed during the test. After a 3-
min rest and another period of initial warm-up at 20% of the
predicted maximal power (PMP) for 3 min, the subject per-
forms 6-min workloads at approximately 30%, 40%, 50% and
60% of PMP. The phase of recovery comprises two periods
during which respiratory and cardiac parameters are monitored:
active recovery at 20% of the PMP during 1 min and passive
recovery (i.e. rest) during the next 2 min. At the end of each
stage, during the fifth and sixth minutes, values of VO
2
and
VCO
2
are recorded. These values are used for calculating the
respective rates of oxidation of carbohydrates and lipids by
applying the following equations of indirect calorimetry [29]:
Carbohydratesmg=min 4:585VCO
2
3:2255VO
2
Lipidsmg=min 1:7012VCO
2
1:6946VO
2
The calculations are performed at the fifth to sixth minute of
each step, because at this time, CO
2
production from bicarbo-
nate buffers compensating for the production of lactic acid
becomes negligible. The increment in carbohydrate oxidation
above basal values appears to be approximately a linear func-
tion of the developed power, and the slope of this relation is
calculated to provide the glucidic cost of Watt [3].
The increase in lipid oxidation adopts a bell-shaped curve:
after peak oxidation, at the highest power intensity, lipid oxi-
dation decreases. The exact mechanism of this reduction is
unknown: a reduction in lipolysis likely explains part of it,
together with a shift of metabolic pathways within the muscle
fiber. From the formula shown above for rate of lipid oxida-
tion, one can deduce that the relation between power (P) and
oxidation of lipids (Lox) is a bell-shaped curve of the form:
Lox A:P1 RER
whose smoothing enables us to calculate the power intensity at
which lipid oxidation becomes maximal, the point at which the
derivative of this curve equals zero [17].
Fig. 1. Exercise calorimetry illustrating Brooks and Merciers crossover
concept [22]. Upper panel, carbohydrate oxidation increases proportional to
power, and lipid oxidation reaches a maximum at a power called LIPOX
max
,
then decreases. Lower panel, when oxidation rates are expressed as a
percentage of total energy supplied to muscles, the percentage carbohydrate
oxidation increases and the percentage lipid oxidation decreases. The two
curves cross at a power intensity at which 70% of energy comes from
carbohydrates and 30% comes from lipids. This transitional zone is called the
crossover point. Both the LIPOX
max
and the crossover point are reproducible in
an individual [7] but easy to modify with training. Training at a level close to
the LIPOX
max
increases the ability to oxidize lipids. Training above the
crossover point increases the ability to oxidize carbohydrates. Knowledge of
those levels, variable among individuals, allows for more specific targeting of
training procedures to enhance carbohydrate or lipid oxidation for therapeutic
purposes.
J.-F. Brun et al. / Annales de radaptation et de mdecine physique 50 (2007) 528534 530
3.2.3. Relevance of this procedure with exercise calorimetry
The basic assumption that underlies exercise calorimetry
is that blood lactate generation during exercise has minimal
influence on RER after 34 min of exercise performed at a
steady state. In this condition, the extra CO
2
production from
blood HCO
3

buffers can indeed be regarded as negligible.

One can calculate that even the fastest increase (approxi-
mately 2 mmol
1
min
-l
) in blood lactate produces only a
3% increase in VCO
2
. Indeed, if we assume that the volume
of distribution of lactate is proportional by a factor of
100 ml kg
l
to body mass and thus represents approximately
8 l, this would mobilize 16 mmol HCO
3

and generate in
6 min approximately 1.8 CO
2
l min
l
. Under these condi-
tions, VCO
2
would increase by less than 0.06 l min
l
, or
approximately 3%. Thus, the increase in RER under these
conditions of exercise is explained almost completely by
the balance between oxidized carbohydrates and lipids, in-
dependent of blood lactate level. The validity of this calori-
metric approach is further confirmed by the classic work of
Romijn et al. [31], who showed in highly trained athletes
that up to 8085% VO
2max
calorimetric calculations based
on respiratory exchanges during exercise closely fit with
more sophisticated measurements involving stable isotopes
(Fig. 2).
Concerning proteins, a comparison of exercise periods at
33% and 66% of VO
2max
shows that their use for oxidation
remains stable at various levels of exercise, which supports
the basal assumption that the balance of substrates may be
interpreted in terms of respective proportions of oxidized fat
and carbohydrates.
3.2.4. A controversy: duration of exercise steps
Our procedure is based on 6-min workloads. However,
other investigators [1,2] have developed a procedure based on
3-min ultra-short workloads. This latter method has been
carefully validated in athletes and healthy sedentary subjects
[2]. However, data are lacking on its validity in very sedentary
patients, in whom the time taken to obtain a steady state of
respiratory exchanges is lengthy. We thus recently compared
calorimetry data obtained with this procedure (secondthird
minutes) with our proposed procedure (fifthsixth minutes)
and found values measured during the 3-min steps poorly
related to values measured during our 6-min steps, because of
overestimation of RER, which can be as high as 0.35. This
shift results in an overestimation of carbohydrate oxidation of
15.8 mg min
1
, on average (this difference can reach
1200 mg min
1
). As well, lipid oxidation is underestimated by
13.9mg min
1
, on average (this difference can reach
250 mg min
1
). Lipid oxidation is poorly related between the
two methods. Thus, among very sedentary patients in whom
these tests were used for targeting physical activity, 3-min
workloads appear too short to allow safe calorimetric calcula-
Fig. 2. Example of the two opposite profiles of exercise calorimetry. Upper panel, metabolically enduring subject, able to oxidize high quantities of lipids during
exercise. Lower pannel, glucodependent subjects, as are usually obese, diabetic, with hypothyroidism, but also athletes training at high-intensity or practicing
intermittent exercise. These profiles are reproducible in a given individual and can be modified by specific training targeted on the basis of these measurements.
J.-F. Brun et al. / Annales de radaptation et de mdecine physique 50 (2007) 528534 531
tions; so our protocol based on 6-min workloads seems prefer-
able [15].
In addition, we recently showed that the estimate of lipid
oxidation at the fifth and sixth minutes of a 6-min step predicts
fairly well the actual lipid oxidation rate that would be
observed over 45 min performed at the same level [21]. The
mean difference between the predicted value and the measured
value is only 4.51 8.7 mg min
1
, which further supports the
use of the 6-min workloads rather than 3-min workloads pro-
posed by Achten et al. [1,2,40]; 3-min workloads seem to be
more appropriate for use in sports medicine and exercise phy-
siology than sedentary patients.
3.2.5. Studies of targeted endurance training at the LIPOX
max
Table 1 shows the results of three studies of training invol-
ving our procedure. In obese adults with metabolic syndrome,
a 2-month targeted exercise training by exercise calorimetry
resulted in a loss of fat mass but not fat-free mass, together
with increased ability to oxidize lipids during exercise [12].
In patients with type 2 diabetes, similar results are obtained
[20]. As well, in obese teenagers, we investigated the impact
of a program associating exercise and diet for 2 weeks in a
specialized clinic followed by 6 weeks of outpatient follow-
up [6]. Teenagers who continued training after the initial 2-
week period exhibited increased ability to oxidize lipids during
exercise, as compared with teenagers who discontinued train-
ing. In another work [7], we evaluated the effect of two differ-
ent training schedules based on different intensities of work
(low and high: 15% below or above the crossover point) asso-
ciated with a hypocaloric diet. All children lost weight. How-
ever, in the group trained at low-intensity, the balance of sub-
strate oxidation was better preserved, and fat-free mass did not
decrease, whereas high-intensity training produced a shift
toward carbohydrate oxidation and decreased fat-free mass.
All these studies show similar effects of low-intensity training
among the populations.
4. Practical aspects of this training procedure
4.1. Schedule
Low-intensity training as we currently prescribe it includes
the following:
A diagnostic session involving exercise calorimetry as
described above, determination of body composition by
bioelectrical impedance, and dietary assessment.
One or two beginning sessions during which patients per-
form the targeted exercise on an ergocycle.
One period of 23 months duration, when the patient trains
at home but remains in weekly contact with the team by
telephone.
A session of re-assessment after training, during which the
tests of the diagnostic session are repeated. This session
allows for evaluating improvements in body composition
and balance of substrates during exercise. Depending on
these results, exercise can then be re-targeted, most of
the time at a higher level, if LIPOX
max
has shifted towards
a higher power intensity. A new, similar cycle, which is
generally more effective, can thus be initiated.
4.2. Is it possible to target exercise without exercise
calorimetry?
Targeting exercise training with calorimetry likely provides
a better understanding of fuel metabolism during training and
helps refine this kind of training strategy. However, this
sophisticated and complex approach is not generalizable to a
large population. Unfortunately, at present, attempts to predict
the LIPOX
max
from crude anthropometric data give inconsis-
tent results [27], largely because of great inter-individual var-
iance in this parameter. Actually, LIPOX
max
is reproducible, in
individuals tested several times, if they have not modified
training habits [7], but its level varies considerably among indi-
viduals.
The development of simplified protocols with less sophisti-
cated explorations would allow the use of this therapeutic
approach on a larger scale. Defining them is undoubtedly one
of the challenges of this area of research.
4.3. Other strategies of training
Regular endurance training, in particular, that well targeted
to LIPOX
max
, improves body composition (decreased fat mass
and maintenance or increased fat-free mass) and enhances the
ability to oxidize lipids during exercise. Other strategies of
training (resistance exercise [1114], SWEET, etc.) are also
Table 1
Effect of 2-month low-intensity endurance training targeted at the level of the LIPOX
max
in three studies of various populations
Dumortier et al. [12] Brandou et al. [6] Jean et al. [20]
Obese and overweight adults with
metabolic syndrome (n = 28, vs. 11
untrained controls)
Obese teenagers (n = 7, vs. seven
untrained controls)
Type 2 diabetics (n = 28, vs. 13
untrained controls)
VO
2max
(%) +18 +17 +18
Weight (kg) 2.6 4.2 1.38
Fat mass (kg) 1.5 4.1 -0.66
Fat-free mass Maintained Maintained Maintained
Waist circumference (cm) 3.53 ND 3.94
Shift in LIPOX
max
(crude power output) (W) +23 +23 +20
Maximal lipid oxidation rate (mg min
1
) +68.5 +50 +34.14
Other effects Increase in insulin sensitivity index
(+73%)
Counteracts the effects of hypocaloric diet
that decreases lipid oxidation
Metabolic syndrome score
reduced 12%
J.-F. Brun et al. / Annales de radaptation et de mdecine physique 50 (2007) 528534 532
useful. Actually these strategies based on exercise at higher
intensity levels have metabolic effects different from those of
low-intensity endurance protocols whose numerous advantages
are well known (and, in our opinion, would be even more
obvious if training were targeted as proposed here). In our
experiments, high-intensity training seems to promote
increased oxidation of carbohydrates [12,13], even if in post-
exercise it may also involve some appreciable use of lipids.
High-intensity training clearly has benefit for circulatory para-
meters and, in particular, improves the blood pressure profile.
Some interesting work [1114,24] shows the efficiency of
high-intensity training on weight control and metabolism.
However, such training is frequently difficult to apply in
terms of patient compliance, because sedentary patients fre-
quently discontinue this kind of training. A closer cardiologic
monitoring is also required, because such patients are at risk
for coronary disorders. Furthermore, Gordon et al. [18]
recently investigated the effect of resistance exercise protocols
on cytokine levels (TNF-, IL-1 and TGF-1). After
16 weeks, trained subjects showed increased muscular mass,
with increased content of both type I and type II fibers, as
well as increased level of inflammatory cytokines. Although
not surprising, since inflammation is involved in muscle repair
and hypertrophy after training and is thus probably beneficial,
this finding suggests caution, because inflammation is also a
factor of insulin resistance and atherogenesis.
Actually, resistance and endurance exercise should not be
opposed and represent two different therapeutic tools, although
recent studies have suggested that they are associated [26,35].
Both strategies have different impacts and are thus complemen-
tary. Despite the growing literature on this topic, the nuances
of their respective use still remain to be defined.
4.4. Therapeutic compliance
Practically, giving an individual new habits of performing
regular exercise, even if targeted by an exercise test, is largely
a problem of therapeutic adherence. First, endurance exercise
on ergocycle is tedious and monotonous. Such exercise
requires motivating the patient according to the context, insist-
ing on the risk of weight regain after the slimming acquired
with such effort, and sometimes also the risk of evolution
towards diabetes [25]. Second, patients must be regularly fol-
lowed by consultation, periodic sessions of reinduction, and
regular telephone contact. Finally, such exercise must be
enjoyable, such as pedaling in front of a television, and varying
the sequence of the procedure.
5. The true challenge: changing inactive people into active
people
The goal of training, even if some aspects of it remain, as
we discussed, somewhat controversial and imperfectly codi-
fied, is ultimately to transform inactive people into active peo-
ple, and to do this in a durable way. Here, many difficulties
arise: obese subjects have a low ratio of muscular mass to
total weight, and being overweight decreases mobility because
of articular problems such as dyspnea, heart maladaptation or
even psychological barriers that prevent a return to exercise.
Thus, this metamorphosis needs to be gradual, carried out
within a personalized approach.
Despite the evolution in this field with the abundant
research in progress, we have now strong evidence that exer-
cise is an important and powerful therapy. Thus, it is important
to implement exercise. Official guidelines, after having been
cautious about such dietary and hygienic procedures whose
importance seemed minor, have now changed, and strongly
support exercise. However, physicians and patients often per-
sist in regarding such exercise programs as unrealistic and
likely to fail. This attitude, combined with the absence of struc-
tures adapted to implement such training on a large scale,
slows the expansion of this major therapy for use in metabolic
diseases, which is pathophysiologically relevant, effective, and
not dangerous. Beside optimizating protocols, overcoming this
persistent defeatist attitude will be a major undertaking over
the next decade in the development of metabolic training.
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