DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW ARTICLE

Diabetes Metab Res Rev 2014; 30(Suppl. 1): 13–23.

Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2514

Physical exercise as therapy for type 2 diabetes

mellitus

Stefano Balducci1,2,3* Abstract

Massimo Sacchetti4
Jonida Haxhi4 Many studies have highlighted the importance of physical activity (PA) for health,
Giorgio Orlando4 and recent evidence now points to the positive improvements associated with
Valeria D’Errico2,3 exercise in type 2 diabetes mellitus (T2DM). However, few physicians are
willing to prescribe exercise as a therapy for diabetic patients. In addition,
Sara Fallucca5
there is a lack of information on how to implement exercise therapy especially
Stefano Menini2 in long-term exercise regimens. The purpose of this manuscript is to summa-
Giuseppe Pugliese2,3 rize standards of exercise therapy for patients with T2DM, both in terms of pre-
1
scribing and monitoring, according to the American College of Sports Medicine
Metabolic Fitness Association, Rome, and the American Diabetes Association guidelines. We present details of the
Italy
exercise therapies used in long-term studies, describing how the parameters
2
Department of Clinical and Molecular for exercise prescription were applied in clinical practice. These parameters
Medicine, ‘La Sapienza’ University, are described in terms of frequency, intensity, duration, mode and rate of
Rome, Italy progression in long-term therapeutic prescriptions. Individual responses to
3
Diabetes Unit, Sant’Andrea Hospital, exercise dose are discussed, and critical issues to be considered in patients with
Rome, Italy underlying disease and in T2DM patients are highlighted. Copyright © 2013
4
Department of Human Movement John Wiley & Sons, Ltd.
Social and Sport Sciences, ‘Foro Italico’
University, Rome, Italy Keywords type 2 diabetes; physical activity; prescribing exercise therapy;
5
Department of Endocrinology and dose–response
Diabetes, University Campus Bio-Medico,
Rome, Italy

*Correspondence to: Stefano Balducci, Introduction

Metabolic Fitness Association, Via
Nomentana 27, 00015 Monterotondo,
The goal of treatment in type 2 diabetes mellitus (T2DM) is to achieve and
Rome, Italy.
maintain optimal blood glucose, lipid and blood pressure levels, and to prevent
E-mail: s.balducci@hctdiabete.it
or delay the development of chronic complications of diabetes [1]. Physical
exercise is central to the management of T2DM to help achieve and maintain
therapeutic goals and improve quality of life [2].
Recent reviews highlight the additional benefits provided by physical exer-
cise used as a therapeutic measure in patients with T2DM [3,4]. At present,
physical exercise therapy is being considered for approval as a prescribed
medication by the Food and Drug Administration in the USA. The key features
of such an approval would necessarily include efficacy for the specific
condition, effectiveness in the target population, recommended dosing for
the designated outcome, mechanisms of action and the safety or adverse event
profile (Table 1). Just as pharmacological therapies and dietary modifications
Received: 23 October 2013
Accepted: 19 December 2013
are individualized for the patient, similarly, a tailored programme of physical
activity could be prescribed for treatment, once approved.

Copyright © 2013 John Wiley & Sons, Ltd.

14
Table 1. Criteria required by the Food and Drug Administration
of the USA to approve physical exercise as a prescribed medication
Efficacy Does it cause a specific health benefit as
demonstrated by adequately designed rando-
mized controlled trials?
Effectiveness Is the specified benefit obtained by a
reasonable percentage of the persons who
undertake the prescribed regimen of exercise?
Who will be the responders and the non-
responders?
Dose What dose of exercise provides a meaningful
benefit for this specific condition? The
prescribed dose needs to be defined in terms
of type, intensity, frequency and duration.
Mechanisms What changes in structure or function caused by
of action the exercise are responsible for the specified
health benefit? In a therapy such as exercise,
there may be multiple mechanisms for a single
health benefit.
Potential adverse What are the medical risks associated with the
events prescribed dose of exercise? What are the
medical contraindications to the prescribed
exercise and what adjustments in dosing need
to be made for specific populations to reduce
adverse events?
Prescription and supervision of exercise therapy ses-
sions, by qualified exercise professionals, has shown that
physical exercise has the greatest effect on glycaemic
control [5–9] in agreement with the latest American
College of Sports Medicine and the American Diabetes
Association guidelines [9], which clearly state that ‘initial
instruction and periodic supervision by a qualified
exercise trainer is recommended for most persons with
type 2 diabetes, particularly if they undertake resistance
exercise training, to ensure optimal benefits to blood
glucose control, blood pressure, lipids, and cardiovascular
risk and to minimize injuries’. The most successful long-
term study of exercise therapy was the Italian Diabetes
and Exercise Study [10,11]. This 1-year trial of super-
vised, facility-based and combined aerobic and resistance
exercise training twice weekly showed that this regime
resulted in improvements in physiological, anthropomet-
ric and mental health-related quality-of-life parameters
and was associated with a low dropout rate [12,13].
The purpose of this review is to highlight critical
lessons learned from the Italian Diabetes and Exercise
Study and, further, to provide definitions and standards
applicable for the American College of Sports Medicine
and the American Diabetes Association guidelines. This
will aid both physicians and exercise therapists in
prescribing, managing and monitoring exercise programmes
for diabetic patients, and suggest some directions for future
research and practice in this area. Firstly, we will define the
essential features of exercise therapy, and then, we will pro-
ceed to describe the parameters necessary for its prescription
in agreement with the American College of Sports Medicine
and the American Diabetes Association guidelines, while
highlighting unanswered questions and issues.
Copyright © 2013 John Wiley & Sons, Ltd.
S. Balducci et al.
Physical activity and exercise therapy:
essential terminology
There is agreement that regular participation in physical
activity and exercise results in positive health-related
outcomes; however, little is known about how much exer-
cise is needed for such positive outcomes. To answer this
question, physical activity or exercise interventions must
be described in a manner that allows comparisons to be
made across the continuum of exercise intensities, types
of exercise and fitness levels. It is also necessary to clarify
the meaning of the various terms associated with physical
activity and exercise for consistent interpretation of exer-
cise intensity and volume in the context of dose–response
issues. Our suggestions are as follows:
Physical activity
Physical activity is defined as any bodily movement pro-
duced by contraction of skeletal muscle that substantially
increases energy expenditure. It includes a broad range of
daily activities (leisure time and occupational).
Leisure-time physical activity
Leisure-time physical activity includes activities under-
taken during free time, based on personal interests and
needs. These activities include activities such as walking,
hiking, gardening, sport or dance programmes as well as
formal exercise training.
The common element is that both physical activity and
leisure-time physical activity result in substantial energy
expenditure, although the intensity and duration can vary
considerably. The intensity of leisure-time physical activity
is described in terms of both absolute and relative intensity.
Absolute intensity. Absolute intensity describes the actual
rate of energy expenditure. It is usually estimated by indi-
rect calorimeter, in which oxygen uptake and carbon diox-
ide production are used to calculate energy expenditure.
Other common expressions used in clinical practice with
the same meaning include the following: oxygen uptake
(L/min), oxygen uptake relative to body mass (mL/kg/min),
kilocalorie or kilojoule per minute, and multiples of resting
metabolic rate. Resting metabolic rate is usually determined
with the subject in the supine position, after an overnight
fast and 8 h of sleep. An oxygen uptake of 3.5 mL/kg/min
is taken as an approximation of basal resting metabolic rate
and is considered as one metabolic equivalent (MET). Meta-
bolic equivalent is defined as ‘the ratio of the work metabolic
rate to the resting metabolic rate’ (Ainsworth) [14]. One
metabolic equivalent is the rate at which adults burn kilocal-
orie at rest: This is approximately 1 kcal/kg of body weight
per hour (expressed as 1 kcal/kg/h). Thus, the metabolic
Diabetes Metab Res Rev 2014; 30(Suppl 1): 13–23.
DOI: 10.1002/dmrr
Exercise as Therapy for Type 2 Diabetes
equivalent value for ‘sitting quietly and watching TV’ is ‘1’,
and means that an individual burns 1 kcal/kg/h during this
activity, whereas the metabolic equivalent value of ‘walking
on level ground at moderate pace’ is 3.3 or 3.3 kcal/kg/h. It
is often difficult to disentangle the plethora of work units
used to define energy expenditure and their conversion.
Table 2 provides conversions for energy units to allow for
basic comparison estimates.
The compendium of physical activities developed by
Ainsworth et al. [14] lists metabolic equivalent values
for over 600 different activities. Each activity listed has
the following information: compendium code, metabolic
equivalent value, category heading and description. For
most activities, metabolic equivalent values are provided
for two different years: 1993 and 2000. This is because
the compendium was first published in 1993, but the
number of major headings and the number of specific
activities [15] have been updated to include revised and ad-
ditional metabolic equivalent values in the year 2000.
When the metabolic equivalent values between 1993 and
2000 differ, it may be advisable to use the metabolic
equivalent value for 2000 unless there is a valid reason to
do otherwise. The metabolic equivalent values in the
compendium can be used to obtain the absolute energy
expenditures associated with all types of physical activities.
Relative intensity. Persons differing in fitness respond in
markedly different ways to an exercise challenge set at a
fixed absolute intensity. An exercise intensity of 10 kcal/
min might be a warm-up for one person but require a
maximal effort by another. Exercise physiologists have
designed experiments to account for such variation by
adjusting the intensity of the exercise relative to some
maximal physiological response. The relative intensity of
aerobic activity has been described in terms of percentage
of maximal oxygen uptake. Across a broad range of fitness
levels, defined in terms of maximal oxygen uptake, many
physiological responses are normalized by expressing the
intensity of exercise as a percentage of maximal oxygen
uptake, which is considered the gold standard definition
of exercise intensity during aerobic exercise. However,
measurements of maximal oxygen uptake during exercise
are limited by the necessity to use expensive equipment
Table 2. Work units converter
From To Conversion
MET mL/kg/min Multiply by 3.5
MET kcal/kg/h Multiply by 1
L/min mL/kg/min Divide by the subject’s body weight
in kg, then multiply by 1000
L/min kcal/min Multiply by 5
MET mL/kg/min Multiply by 3.5
MET kcal/min Multiply by 3.5 and by the subject’s
body weight in kg, then divide by 200
Copyright © 2013 John Wiley & Sons, Ltd.
15
(metabolimeters); as a result, it is often more practical
to estimate metabolic intensity using the percentage of
heart rate reserve or the percentage of maximal heart rate
as outlined as follows.
• Percentage of heart rate reserve. The heart rate reserve is
calculated by subtracting resting heart rate from
maximal heart rate. The percentage of heart rate
reserve is a percentage of the difference between
resting and maximal heart rate, and is calculated by
subtracting resting heart rate from the exercise heart
rate, dividing by the heart rate reserve, and multiply-
ing by 100. The percentage of heart rate reserve has
been proposed to be an approximate percentage of
oxygen uptake reserve (defined as the difference between
maximal oxygen uptake and oxygen uptake at rest).
• Percentage of maximal heart rate. Because of the linear
relationship between heart rate (above approximately
110 beats per minute) and oxygen uptake during
dynamic exercise, investigators and clinicians use a
simple percentage of maximal heart rate as an estimate
of the percentage of maximal oxygen uptake for setting
exercise intensity [18,19]. To translate percentage of
maximal heart rate values into percentage of maximal
oxygen uptake, however, the relationship between
these two physiological parameters must be known
(i.e. heart rate/oxygen uptake).
• Rating of perceived exertion scale [16,17]. It is not
viewed as a substitute for prescribing exercise intensity
by heart rate, but once the relationship between the
heart rate and rating of perceived exertion has been
established, rating of perceived exertion can be used
in its place [20]. However, the rating of perceived
exertion may not consistently translate to the same
intensity for different modes of exercise, so there may
not be an exact matching of the rating of perceived
exertion to a percentage of maximal heart rate or the
percentage of heart rate reserve [16].
Exercise training. Exercise training is a subcategory of
leisure-time physical activity in which planned, structured
and repetitive bodily movements are performed to
improve or maintain one or more components of physical
fitness (i.e. cardiorespiratory, strength and flexibility):
• Cardiorespiratory fitness reflects the ability of the
cardiovascular and respiratory systems to supply oxygen
to the working muscles during dynamic exercise. It is
usually measured by indirect calorimetry in a laboratory
setting, and expressed as maximal aerobic power or
maximal oxygen uptake, which is the highest rate of
oxygen uptake achieved during heavy dynamic exercise.
However, cardiorespiratory fitness can also be estimated
from peak power achieved on a cycle ergometer or from
Diabetes Metab Res Rev 2014; 30(Suppl 1): 13–23.
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16
time on a standard treadmill test, and with less precision,
using sub-maximal tests in which the heart rate to
workload relationship is extrapolated to an age-predicted
end point.
• Muscular strength is a measure of a muscle’s ability to
generate force. It is generally expressed as maximal vol-
untary contraction for isometric measurements and as
the one-repetition maximum for dynamic measurements.
• Resistance exercise (training) is an anaerobic training
designed specifically to increase muscular strength,
power and endurance by varying the resistance; the
number of times the resistance is moved in a single
set of exercises; the number of sets performed; and
the rest interval between sets.
• Flexibility is the range of motion in a joint or group of
joints or the ability to move joints effectively. Flexibil-
ity is an important part of reducing injury risk and
soreness resulting from physical activity. It can be
improved with stretching exercises but does not increase
muscle strength.
Occupational physical activity
Occupational physical activity is an activity associated
with an occupation or job. In contrast to the 60-min time
frame over which the categories of intensity were devel-
oped for aerobic activities, the time frame for occupa-
tional physical activity is usually within the 8 h/day.
Some studies use the compendium of physical activity to
assign metabolic equivalent values for specific occupa-
tional settings to obtain energy expenditures associated
with occupational physical activity [15].
Exercise therapy: characterizing the dose
An important question when prescribing exercise is what
is the optimal therapeutic dose required to produce a spe-
cific health benefit? Typically, when considering exercise
dose in relation to health outcomes, exercise is character-
ized by type, intensity and volume (session duration and
frequency), as seen in the American College of Sports
Medicine and the American Diabetes Association guide-
lines (Table 3).
Type of exercise
As muscle contractions have both mechanical and meta-
bolic effects, these have been used to classify the type of
exercise performed, a situation that can cause confusion.
Mechanical classification assesses whether the muscle con-
traction produces movement of the limb or not: isometric
(same length) or static exercise if there is no movement
of the limb, or dynamic (isokinetic) exercise if there is
movement of the limb. A muscle contraction can either
be concentric (shortening of the muscle fibres) or eccentric
(lengthening of the muscle fibres). Metabolic classification
Copyright © 2013 John Wiley & Sons, Ltd.
S. Balducci et al.
subdivides according to the metabolic pathways used to
transform energy. From this point of view, exercise is
often classified as aerobic or anaerobic training.
• Aerobic exercise training (prevalence of oxidative
metabolic pathway) involves large muscle groups in
dynamic activities that result in substantial increases
in heart rate and energy expenditure. Regular partici-
pation in aerobic exercise results in improvements in
the function of the cardiovascular system and skeletal
muscles, leading to central and peripheral adaptations
that result in an increase in endurance performance.
• Anaerobic exercise training (glycolytic and phosphagens
pathways) involves very high-intensity exercise that
uses glycogen and phosphocreatine stores for the
majority of the energy provided.
• Resistance exercise (training) is an anaerobic training
designed specifically to increase muscular strength,
power and endurance by varying the resistance; the
number of times the resistance is moved in a single
set of exercises; the number of sets performed; and
the rest interval between sets.
Whether or not an activity is aerobic or anaerobic
depends primarily on its intensity relative to the capacity
of the muscle for that type of exercise. Most activities
involve both static and dynamic contractions as well as
aerobic and anaerobic metabolism. Thus, activities tend
to be classified on the basis of their dominant metabolic
and/or mechanical characteristics.
Intensity of exercise
The intensity of an activity can be described in both abso-
lute and relative terms. In absolute terms, it is the magni-
tude of the increase in energy expenditure necessary to
perform the activity (aerobic or endurance exercise) or
the force produced by the muscle contraction (resistance
or strength exercise). The increase in energy expenditure
is usually determined by measuring the increase in
oxygen uptake, which is expressed in units of oxygen or
converted to a measure of heat (kcal) or a measure of
energy expenditure (kJ). The force of the muscle contraction
is commonly quantified by measuring how much weight is
being moved or the force exerted against an immovable
object and expressed in kilogrammes, newton (N) or
Newton metre (torque). In relative terms, the intensity of
the activity is generally expressed in relation to the capacity
of the person performing the activity.
For energy expenditure, the intensity is usually
expressed as a percentage of the person’s aerobic power
(percentage of maximal oxygen uptake; see Table 2).
Because there is a linear relationship between the increase
in heart rate and the increase in oxygen uptake during
dynamic exercise, the percentage of maximal heart rate,
Diabetes Metab Res Rev 2014; 30(Suppl 1): 13–23.
DOI: 10.1002/dmrr
 Table 3. The American College of Sports Medicine and the American Diabetes Association: brief summary of recommendations based on the joint position statement on
exercise and type 2 diabetes mellitus

Combined aerobic and resistance training

Aerobic exercise training Resistance exercise training and other types of training Flexibility training

1.1 Frequency. Aerobic exercise should be
performed at least 3 days/week with no
more than 2 consecutive days between
bouts of activity.
1.2 Intensity. Aerobic exercise should be at
least at moderate intensity, corresponding
2.1 Frequency. Resistance exercise should be
undertaken at least twice weekly on non-
consecutive days, and ideally three times a
week, as part of a physical activity programme
for individuals with type 2 diabetes, along with
regular aerobic activities.
2.2 Intensity. Training should be moderate
(50% of one-repetition maximum or vigorous
Inclusion of both aerobic and resistance
exercise training is recommended. Combined
training thrice weekly in individuals with type
2 diabetes may be of greater benefit to blood
glucose control than either aerobic or
resistance exercise alone.
Daily movement (unstructured activity)
Flexibility training may be included as part of
a physical activity programme, although it
should not substitute for other training.
Flexibility exercise combined with resistance
training can increase range of motion in
individuals with type 2 diabetes and allow
individuals to more easily engage in
activities that require greater maximum

Copyright © 2013 John Wiley & Sons, Ltd.

approximately to 40–60% of maximum (75–80% of one-repetition maximum for range of motion around joints.
oxygen uptake (for most people with type 2 optimal gains in strength and insulin action.
Exercise as Therapy for Type 2 Diabetes

diabetes, brisk walking is a moderate-

intensity exercise). Additional benefits may
be gained from vigorous exercise (>60% of
maximum oxygen uptake), suggesting that
those already exercising at a moderate
intensity should consider undertaking some
vigorous PA to obtain additional benefits.
1.3 Duration. Individuals with type 2
diabetes should engage in a minimum of
150 min/week of exercise undertaken at
moderate intensity or greater to achieve
optimal coronary heart disease risk
reduction. Individuals with higher aerobic
capacities (>10 metabolic equivalents)
may be able to exercise at a higher
absolute intensity for less time and
achieve the same benefits.
1.4 Mode. Any form of aerobic exercise
(including brisk walking) that uses large
muscle groups and causes sustained
increases in heart rate is likely to be
beneficial, and undertaking a variety of
modes of physical activity is recommended.
1.5 Rate of progression. At present, no study
on individuals with type 2 diabetes has
compared rates of progression in exercise
intensity or volume. Gradual progression of
both is advisable to minimize the risk of
injury, particularly if health complications
are present, and to enhance compliance.
2.3 Duration. Each training session should Individuals with type 2 diabetes are
minimally include five to ten exercises encouraged to increase their total daily,
involving the major muscle groups (in the unstructured physical activity to gain
upper body, lower body and core) and additional health benefits. Non-exercise
involve completion of 10–15 repetitions to activity thermo genesis (i.e. energy
near fatigue per set early in training, expending for activities of daily living) can
progressing over time to heavier weights create a greater daily volume of physical
(or resistance) that can be lifted only 8–10 activity.
times. A minimum of one set of
repetitions to near fatigue, but as many as
three to four sets, is recommended for
optimal strength gains.
2.4 Mode. Resistance machines and free To gain additional health benefits
weights (e.g. dumb-bells and barbells) can individuals with type 2 diabetes should be
result in fairly equivalent gains in strength encouraged to increase their daily volume
and mass of targeted muscles. of unstructured physical activity
2.5 Rate of progression. To avoid injury,
progression of intensity, frequency and
duration of training sessions should occur
slowly. In most progressive training, increases
in weight or resistance are undertaken first
and only once when the target number of
repetitions per set can consistently be
exceeded, followed by a greater number of
sets and lastly by increased training
frequency. Progression for 6 months to
thrice-weekly sessions of three sets of eight
to ten repetitions performed at 75–80% of
one-repetition maximum on eight to ten
exercises may be an optimal goal.

DOI: 10.1002/dmrr
Diabetes Metab Res Rev 2014; 30(Suppl 1): 13–23.
17
18
or heart rate reserve (maximal heart rate minus resting
heart rate), is also used as an expression of exercise inten-
sity relative to the person’s capacity.
For muscle force, the relative intensity of the contrac-
tion is expressed as a percentage of the maximal force that
can be generated for that activity (percentage of maximal
voluntary contraction or percentage of one-repetition
maximum; see Table 3).
Intensity then is a key factor in the responsiveness to
exercise for achieving health outcomes. Not only does
intensity play a major role in producing the favourable
adaptations to exercise but it also has a major role in the
various health risks produced by increases in exercise.
As stated earlier, adaptations occur when the exercise
stimulus to a specific tissue or system is greater than that
usually experienced. Thus, for a person who habitually
walks at 4.8 km/h for 3.2 km, an increase in walking
speed (intensity) to 6.4 km/h will act as stress on the
oxygen transport system, substrate (carbohydrate and
lipids) processing systems and oxidative processes in leg
skeletal muscle fibres, so producing adaptations in these
systems. Once adaptations have been made to this
intensity of exercise, increases in intensity will be needed
to produce additional intensity-dependent adaptations.
In most experimental studies evaluating the effects of
increased exercise on various biomarkers of health,
intensity is expressed relative to each person’s capacity.
However, in most, if not all, prospective observational
studies, exercise intensity is expressed in absolute terms
(no adjustment made for each person’s exercise capacity).
These differences in methodology prevent direct compari-
son of dose–response data from these two major sources
of information. While there have been major attempts to
standardize the assignment of intensity to various
activities [15] and to classify activities into various inten-
sity categories (light, moderate and heavy; see Table 2)
[20], there are still meaningful differences in the classifi-
cation of activities such as walking at 5.6 km/h or what
walking speed is meant by brisk walking. Standardization
of these classifications is essential for establishing the
relationship between intensity and health outcomes. For
some outcomes, it appears that the total amount of
exercise performed is more important than the intensity
at which (above a non-specific minimal level) the exercise
is performed [21].
The importance of exercise intensity is debatable. For ex-
ample, a comparison between low-to-moderate-intensity
and moderate-to-high-intensity training programmes in
patients with T2DM showed similar non-significant
improvements between groups in clinical outcomes of
low-density lipoprotein cholesterol, cardiovascular fitness
and skeletal muscle oxidative capacity [22]. Likewise, data
from the Italian Diabetes and Exercise Study indicate that
in low-fitness individuals, such as sedentary subjects with
Copyright © 2013 John Wiley & Sons, Ltd.
S. Balducci et al.
T2DM, moderate-to-high-intensity exercise, in comparison
with low-to-moderate intensity exercise, produced only
clinically marginal, although statistically significant,
improvements in HbA1c, triglycerides and total cholesterol
but not in other risk factors and coronary heart disease risk
scores. However, intensity was not an independent predic-
tor of reduction of any of these parameters. It appears that
increasing exercise intensity is not harmful and the rate of
adverse events is similar. Thus, exercise intensity may be
seen as a less important issue than volume and type of
training, when exercise is applied as a form of therapy in
these individuals [23].
High-intensity interval training. High-intensity interval
training involves bouts of high-intensity exercise (15 s to
4 min; ≥90% maximal oxygen uptake) followed by a
recovery period (40–50% maximal oxygen uptake or
passive recovery) of equal or longer duration than the
work interval. Although the net effect of high-intensity
interval training is aerobic, periodic excursions involving an-
aerobic energy pathways theoretically ‘push’ mitochondria
to greater improvements in exercise capacity, mitochondrial
biogenesis, enzymatic markers associated with glycolysis,
aerobic metabolism and beta-oxidation [24]. Little is known
regarding the use of low-volume, high-intensity interval
training in T2DM [25,26], but it is conceivable that high-
intensity interval training may provide greater changes in
specific metabolic pathways associated with glycolysis,
aerobic metabolism, beta-oxidation and mitochondrial
biogenesis in these patients [24].
Volume of exercise (session duration and frequency)
The product of absolute intensity, duration and frequency
yields the total energy expenditure associated with a
physical activity over a specified time and is taken as a
measure of the volume of physical activity. Volume may
be described in the following units:
• Kilocalories. For a 60-kg person doing slow ballroom
dancing (three metabolic equivalents) for 60 min,
three times per week, the volume is 540 kcal/week
for this activity (3 kcal/kg/h × 60 kg × 3 h/week).
• Metabolic equivalent-minute. Obtained by multiplying
the number of minutes an activity is performed by the
energy cost in metabolic equivalents. The earlier exam-
ple yields 540 metabolic equivalents per minute per
week (three metabolic equivalents × 180 min/week).
For a 60-kg person, metabolic equivalent per minute
yields the same value as kilocalorie/week.
• Metabolic equivalent-hour. Calculated by multiplying
the number of hours an activity is performed by the
energy cost in metabolic equivalents. For the example
earlier, it would be nine metabolic equivalents per hour
per week (three metabolic equivalents × 3 h/week).
Diabetes Metab Res Rev 2014; 30(Suppl 1): 13–23.
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Exercise as Therapy for Type 2 Diabetes
Session duration and frequency have traditionally been
considered when prescribing an exercise plan that focuses
on performing a discrete bout of exercise three or more
times per week [18]. For enhancing cardiorespiratory
function and for cardiovascular disease prevention and
rehabilitation, a session duration of 20–60 min of moder-
ate-to-vigorous-intensity endurance-type exercise performed
3 or more days per week has been the typical recommenda-
tion. When performing resistance exercise, duration is not
measured in time but by the number of exercises
performed, the number of sets per exercise and the number
of repetitions per set (Table 3).
Key questions regarding the role of session duration and
frequency in response to exercise include the following:
• How short can a bout of endurance-type exercise be and
still contribute to specific health outcomes (e.g. does stair
climbing for 1 min per session 20 times per day provide
benefits similar to a single session per day of 20 min?)?
• Do sessions of long duration (90 min) on 1 or 2 days
per week provide similar benefits as shorter 30-min
sessions performed 5 to 6 days per week? and
• Do multiple short bouts of exercise, spread throughout
the day, provide more benefit than a single longer bout?
If the key stimulus for health benefits is exercise
volume, above some minimal intensity threshold, then a
wide variety of exercise profiles can be encouraged for
promoting health [21].
Key questions regarding the role of accumulation or
volume include the following:
• What are the health benefits produced by accumulating
30 or more minutes of exercise per day performing multi-
ple short (≤5 min) bouts of moderate-intensity exercise?
• Do multiple short bouts of exercise versus one longer
bout per day produce more favourable acute responses?
• What are the limits of the accumulation approach in terms
of the minimum duration of each exercise session? and
• Is exercise timing, especially in relation to the time
from a meal, important for controlling postprandial
metabolic events and 24-h glycaemic control [27]?
Characteristics of the exercise
response
Important questions about exercise response include the
following:
• What are the key health-related responses for which a
required exercise dose is desired?
• How does the exercise dose that produces changes in
individual biological benefits relate to clinical benefit?
Copyright © 2013 John Wiley & Sons, Ltd.
19
• What is the basis for substantial inter-individual varia-
tions in the response to a specific exercise dose? and
• What is the health benefit to health risk relationship for
various doses of exercise?
The particular desired outcome must be taken into
account when deciding how much exercise is enough,
due to the specificity of the exercise effect. For example,
the stimulus for changes in fat and carbohydrate metabo-
lism is most likely to be responsive to increases in total
energy expenditure above some intensity threshold,
whereas changes in bone density are likely due primarily
to the stress placed on bone, by forces working against
gravity or by vigorous muscular contractions. In addition,
individual characteristics, such as age, gender, body com-
position or size, diet, smoking habits, use of medications,
clinical status and baseline exercise and fitness levels,
may substantially influence the dose–response relation-
ship for exercise and health-related outcomes.
Exercise in patients with underlying
clinical conditions
For some clinical conditions such as chronic heart disease,
there appear to be a number of exercise-induced biologi-
cal changes that contribute to a reduction in morbidity
and mortality. These changes include, but are not limited
to, improvements in the plasma lipoprotein profile, a
decrease in insulin resistance, reductions in blood pressure,
increased coronary blood flow and decreases in myocardial
oxygen demand [28]. It is likely that the dose–response
relationship varies with these biological changes; for exam-
ple, the dose–response relationship for clinical events
would include integration of the dose–response relation-
ship for all of the biological mechanisms. Thus, the dose–
response relationship for any one biological variable does
not necessarily represent the dose–response relationship for
a reduction in overall clinical events in chronic heart disease.
Key issues include knowing how the dose–response
relationships, for specific biological risk factors, relate to
the dose–response relationship for clinical outcomes such as
myocardial infarction, stroke, non-insulin-dependent diabetes
mellitus and site-specific cancers. All of these major clinical
entities are likely to benefit through a variety of exercise-
induced biological changes. Further research necessary to
establish which biological changes contribute the most to
the reduction in risk for these clinical conditions is warranted.
Inter-individual variations in response
to a specific exercise dose
Typically, the results of randomized controlled trials,
evaluating the effects of exercise training on a specific
Diabetes Metab Res Rev 2014; 30(Suppl 1): 13–23.
DOI: 10.1002/dmrr
20
health-related outcome, compare the mean changes in the
exercise group versus the mean changes in the control
group. When the mean change in the exercise group is
greater than the mean change in the control group, then
that dose is said to be efficacious in producing the specific
outcome. However, inside the exercise group itself, there
can be substantial variation in the change among subjects
exposed to the same exercise stimulus, with some subjects
having no change or even a decrease, whereas others may
have changes much greater than the mean. There is an
inter-individual variability in the ability to improve cardio-
respiratory fitness and cardiometabolic and diabetes risk
factor profiles in response to regular exercise. The issues
of different individual responses to regular exercise, and
of the existence of a fraction of people who might experi-
ence adverse changes in cardiovascular and diabetes risk
factors during exercise intervention, have never been
extensively addressed.
Balancing benefits and risks
Prescribing exercise can be a double-edged sword with
regard to health status. As the intensity and amount of
exercise performed is increased, the greater is the risk of
injury, especially musculoskeletal injuries; cardiovascular
complications can also occur in those with underlying dis-
ease. Intensity is of particular concern when attempting to
establish the optimal dose of exercise for health outcomes,
because it is the major contributor to exercise-induced
medical complications. Thus, dose–response assessment
should consider not only which dose induces the greatest
health benefit but also the risk profile relative to that
dose. It is possible that the same type of exercise at higher
intensities (running) may provide greater benefit for a spe-
cific biological outcome, but at moderate intensities (brisk
walking), it may provide the best overall health benefit in
at-risk populations because of its lower risk profile [29].
Key issues include the following:
• establishing the risk profile for various exercise regi-
mens in different populations, especially in the elderly;
• documenting exercise doses that can provide benefit at
minimal risk in selected at-risk populations; and
• developing algorithms for the prediction of risk associated
with different exercise regimens for specific populations.
Exercise dose–response relationship
in type 2 diabetes mellitus
When considering the response to exercise in diabetes, it
is important to establish the priority for health outcomes,
Copyright © 2013 John Wiley & Sons, Ltd.
S. Balducci et al.
the relationship of the dose–response for individual
biological variables in relation to the dose–response for
clinical outcomes, the basis for substantial inter-individual
variations in the response to a specific exercise dose and
the health benefit to health risk relationship for various
doses of exercise.
Two important studies have been published on dose–
response outcomes associated with long-term exercise
therapy among diabetes patients. Di Loreto et al. [30]
evaluated the impact of different amounts of energy
expenditure of aerobic physical activity (metabolic equiv-
alents per hour per week) on anthropometric features
(body weight, body mass index and waist circumference)
and physiological outcomes (fasting plasma glucose;
HbA1c; systolic and diastolic blood pressure; resting heart
rate; serum total, low-density lipoprotein and high-
density lipoprotein cholesterol; serum triglycerides and
10-year coronary heart disease risk), in 182 patients with
T2DM. At baseline, subjects were divided into six groups
(A–F), with increments in metabolic equivalents (thus,
group A = no activity and group F = 58.3 ± 1.8 metabolic
equivalents per hour per week). After 2 years, the entire
intervention group increased energy expenditure by
26 ± 2 metabolic equivalents, showing strong significant
reductions in all parameters evaluated, a ~3% reduction
in 10-year coronary heart disease risk and a significant
increase in high-density lipoprotein cholesterol. There
was no significant change in any of the health parameters
examined in the least active groups A (no activity) and B
(6.8 ± 0.3 metabolic equivalents). Instead, the moderately
active group C had accumulated 17.1 ± 0.4 metabolic equiv-
alents and obtained significant improvements only in
HbA1c, systolic and diastolic blood pressure, total choles-
terol and 10-year coronary heart disease risk. Significant
improvements in all measured parameters were obtained
only from groups D to F (27 ± 0.5 metabolic equivalents).
These results indicate that more exercise is better, but the
question still remains, how much is ‘more’? This question
was studied by the Italian Diabetes and Exercise Study
investigators, taking into account variables such as individ-
ual response, intensity and duration, as outlined by the
American College of Sports Medicine and the American
Diabetes Association guidelines (Table 3).
In the Italian Diabetes and Exercise Study [10], accu-
mulated physical activity, with a mean volume of 20 met-
abolic equivalents per hour per week in the exercise group
(non-supervised conditioning physical activity plus aero-
bic and resistance training supervised physical activity),
produced significant improvements in all parameters mea-
sured, while 10 metabolic equivalents accumulated in the
control group (almost exclusively aerobic non-supervised
physical activity) only marginally improved some parame-
ters. The difference in energy expenditure between the
two groups seemed to explain the different outcome in
Diabetes Metab Res Rev 2014; 30(Suppl 1): 13–23.
DOI: 10.1002/dmrr
Exercise as Therapy for Type 2 Diabetes 21

terms of cardiovascular risk profile, as indicated by the according to quintiles of exercise volume in metabolic
analysis per quintiles of metabolic equivalents for each equivalents per hour per week after adjustment for base-
risk factor. The probability of reaching specific targets line values showed a variable trend for the different

Figure 1. Probability of reaching specific targets according to quintiles of exercise volume (METs/h/week). BMI, body mass index;
SBP, systolic blood pressure; DBP, diastolic blood pressure; COL, cholesterol; LDL, low-density lipoprotein; HDL, high-density
lipoprotein; TRIG, triglycerides

Figure 2. Comparison of total coronary heart disease (CHD) score delta changes (median) between PA volume (METs/h/week) II–V
and I quintiles

Copyright © 2013 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2014; 30(Suppl 1): 13–23.
DOI: 10.1002/dmrr
22 S. Balducci et al.

cardiovascular risk factors, with a dose-dependent effect
for most of them (Figure 1). For a calculated 10-year
coronary heart disease risk score, a statistically signifi-
cant decrease was observed only from the third quintile
12.3–18.2 metabolic equivalents per hour per week,
mean 15.2 (Figure 2). This finding suggests that in
subjects with T2DM, the amount of physical activity
recommended by the current guidelines (i.e. 150 min/
week of moderate intensity corresponding to about
10 metabolic equivalents per hour per week) may be suffi-
cient to reduce some modifiable cardiovascular risk factors
but may not be enough to significantly reduce the 10-year
coronary heart disease risk. In this class of patients at high
coronary heart disease risk, the largest volumes of physical
activity (~20 metabolic equivalents per hour per week) are
needed to obtain the greatest health benefits.
Conclusions
timing, progression and precautions, as suggested by the
current recommendations. The exercise prescription
should be personalized, based on individual habits, prefer-
ences, motivation and tolerance, rather than a general
prescription describing exercise duration, intensity and
frequency, based on clinical testing.
Successful exercise interventions in T2DM tend to
require intensive counselling and supervision from medical
or exercise professionals; some of the successes of these
programmes are related to the higher patient compliance
associated with supervised programmes, compared with
non-supervised programmes. While research investigating
the possible health benefits and long-term financial viability
of incentive-based programmes in T2DM would be
welcome, due consideration must be given to the need to
promote adherence to guidelines for sustainable, long-term
lifestyle change, rather than short-term intensive exer-
cise programmes. Future possibilities in this area include
the following:

Even though the benefits of physical exercise as a thera-
peutic measure for patients with T2DM are well-known
and accepted, it is difficult to put exercise recommenda-
tions into action for a number of reasons. Lack of patient
compliance, insufficient knowledge among diabetologists
and exercise professionals and lack of dedicated facilities
have all been indicated as important limitations to the
application of the recommendations given in the American
College of Sports Medicine and the American Diabetes
Association position statement (Table 3).
Prescribing exercise is not generally undertaken, either
by the general practitioner or by the diabetologist. This
may be because there is insufficient awareness of the
benefits of exercise or because there is a lack of specific
knowledge about current recommendations. To prescribe
exercise in the context of diabetes, it is important to con-
sider how the physiology of exercise training interacts
with both the pathophysiology and medical management
of the patient’s chronic disease. Thus, prescriptions, when
suggested, are generic and more oriented towards
‘physical activity’ rather than ‘exercise therapy’, without
appropriate indication about type, intensity, frequency,
• A more systematic investigation of personal character-
istics, both genetic and non-genetic, that might
influence the inter-individual variation in dose–response
for specific health and performance outcome.
• Investigation of the physiological effects and practical
benefits of exercise training of different intensities
in T2DM.
• The study of the metabolic profiles of patients with
T2DM with one or more cardiovascular risk factors
who are responsive or non-responsive to supervised
exercise.
Acknowledgement
The authors thank Philippa Mungra in the preparation of the
manuscript
Conflicts of interest
The authors have no conflicts of interest to declare.

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