The
world is in the midst of a global diabetes epidemic. Its occurrence,
particularly type 2 diabetes, continues to rise unrelentingly in most developed
and developing nations (Simpson et al
2003). Current estimates of the global prevalence of type 2 diabetes calculate
that approximately 250 million people are affected, and this number is expected
to rise to some 380 million people by the year 2025 (Praet and Van Loon 2007).
Diabetes is currently the 9th leading cause of death worldwide (WHO
2012), and current epidemiological patterns show that the incidence of diabetes
is progressively increasing in young and middle-aged people (Ehrman et al 2003). Death rates for young
people with diabetes are staggeringly high in comparison to healthy individuals,
with observations that in excess of 15% of people that develop diabetes before
30 years of age will die before they reach 40. The economic and social cost of
this disease is huge, diabetes is associated with many severe clinical
complications which result in disability and reduced life expectancy, placing
an enormous burden on the economy in terms of healthcare costs and reduced
productivity in the workplace (Simpson et
al 2003). In Ireland alone, the cost of treating this disease accounts for
10% of the entire health budget totaling €1.4 billion per annum (Nolan et al 2006). Physical inactivity is one
of the most important modifiable risk factors for primary prevention of type 2
diabetes. Exercise has long been considered to play a key role in the treatment
and prevention of diabetes alongside diet and medication, however high-quality
research on the importance of physical activity and exercise in this area was
lacking until recently (Sigal et al
2006). The focus of this article will be
on the pathophysiology of the disease, the mechanisms through which exercise
acts as a therapy, the role of exercise and in particular current
recommendations in relation to the frequency, intensity, time, and type of
exercise, as well as future recommendations to help combat this disease.
Figure
1. Increases in the prevalence of diabetes
from 1995-2010 (Simpson et al 2003)
Pathophysiology
The
pathophysiology of Type 2 Diabetes Mellitus (T2DM) is complex and controlled by
many factors, including both genetic and environmental components that affect
β-cell function and tissue insulin sensitivity (Frontera et al 2006). T2DM is characterized by defects in both insulin
action and insulin secretion, which leads to a gradual increase in plasma
glucose levels over time (Ehrman et al
2003). The role of insulin is to transport glucose into the cell. Insulin is a
peptide hormone that is secreted by the β-cells in the islets of langerhans in
the pancreas. Each time we eat, insulin is released into the bloodstream to
induce the liver, muscles, and adipose tissue to remove glucose from the blood
for metabolism or storage (Widmaier et al
2008). In a normal fed state there is an increase in blood glucose coming from
the gut, insulin binds with its receptor which is embedded in the plasma membrane
of the cell. Once insulin is bound to its receptor, it initiates the signaling
pathway that causes the vesicles containing GLUT-4 to translocate to the plasma
membrane and allow glucose to enter the cell.
In
an insulin resistant state, where insulin action is not working properly, there
is still the same or even an increased production of insulin from the pancreas
in response to an increase in blood glucose but there is no translocation of
the internal vesicle containing GLUT-4 to the plasma membrane, thus glucose
cannot enter the cell (Frontera et al
2006). However, there is less glycogen synthesis because of the decreased
uptake of glucose into the liver. Since insulin is not working effectively, the
liver still maintains gluconeogenesis, thus there is already plenty of glucose
in the blood but the liver is releasing even more causing hyperglycaemia
(McArdle et al 2010). In a
hyperglycaemic state glucose can attach to different proteins and glycosylate
them. This glycosylation affects the proteins function and ability to work
properly. De Novo lipogenesis still occurs because the effect of insulin to act
on the cell is reduced, resulting in the uptake of fatty acids into the muscle
causing a build-up of intra-myocellular lipid stores (Williams and Pickup 2004).
β-cell
dysfunction can occur up to 10 years before hyperglycaemia takes place, this
alteration is evident with a reduced insulin response to glucose (Scheen 2003).
In the early stages of impaired β-cell function there is a reduced insulin
response to glucose, causing increased postprandial hyperglycaemia. As the
dysfunction progresses to its later stages, prolonged hyperglycaemia triggers
insulin secretion to be sustained for a longer time, this has been hypothesized
to overwork the β-cell and impair its function (Leahy 1996). A progression from
IGT to T2DM occurs due to a combination of insulin resistance and β-cell
dysfunction, increased β-cell insulin secretion can’t maintain its high rates
in response to glucose and T2DM develops (Ehrman et al 2003). By the time the disease is diagnosed, β-cell function
will typically already be reduced by approximately 50%, and a progressive
linear decrease of β-cell insulin secretion capacity over subsequent years can
explain the deterioration of blood glucose control (Bilous and Donnelly 2010, Scheen
2003).
There
are a number of environmental and genetic risk factors that may contribute to
the development on T2DM. Some of these are non-modifiable risk factors such as
ethnic origin, age, and family history. However, there are several modifiable
risk factors associated with lifestyle choices that can lead to the development
of T2DM, namely, obesity, physical inactivity, and diet. In the majority of western
populations, more than 60% of new cases of T2DM are occurring in obese patients
(Watkins et al 2004). Obesity is
achieved through overfeeding of modern calorie dense food, coupled with a
sedentary lifestyle, resulting in prolonged positive net energy balance (Scheen
2003). While obesity has been recognized as an important determinant of insulin
sensitivity, the distribution of body fat appears to be the decisive factor. The
greatest risk of diabetes is associated with central obesity in which fat is
deposited intra-abdominally (Williams and Pickup 2004). Excess fat in the
visceral region releases greater amounts of non-esterified fatty acids (NEFAs)
through lipolysis which increases gluconeogenesis in the liver and reduces
glucose uptake at the muscular and hepatic sites (Scheen 2003). Long term
positive energy balance not only increases fat stores in the adipose tissue but
also results in an increase in intramuscular triglyceride storage. In addition,
lipids can accumulate in other tissues and affect their normal function, hepatic
steatosis is regular in obese subjects, and non-alcoholic fatty liver disease
is now linked with insulin resistance (Ravussin and Smith 2002). The severity
of insulin resistance in the tissues is related to the degree of intramuscular
triglyceride deposits, and interestingly increased fatty deposits in the
pancreatic islets has been reported as a contributing factor in β-cell
dysfunction (Unger 2002).
Exercise
as a Therapy
Skeletal
muscle is the primary site for the disposal of glucose in the body. As discussed
already, in the insulin resistant state this function is impaired. However,
exercise, or more specifically, muscle contraction, has an insulin-like effect.
Even though individuals with T2DM are resistant to insulin, they are not
resistant to the effect that exercise has on glucose utilization (Sigal and
Kenny 2004). Muscle contraction activates AKT independent of insulin, and
invokes the translocation of the GLUT-4 receptor to the sarcolemma and
t-tubules allowing glucose transport to take place (Henriksen 2002). The signal
for translocation of GLUT-4 during exercise is different from the insulin
mediated function, and does not require phosphorylation of the insulin receptor
(Rockl et al 2008). A single bout of
exercise can have a significant glucose lowering effect in individuals with
T2DM, as well as lowering plasma insulin concentrations during the activity.
There is one main difference between the insulin effect and exercise effect.
Insulin has a half time in circulation of approximately 7 minutes, so as soon
as it is produced, the body must utilize it. Once it is withdrawn, glucose
uptake is suppressed. Exercise has a different effect, it has been shown that a
single bout of exercise can have a residual effect on glucose uptake for up to
72 hours (Sigal and Kenny 2004).
Exercise
increases energy expenditure, skeletal muscle is the largest organ in the body,
much bigger than the liver and adipose tissue. The larger the amount of muscle
mass engaged in exercise, the more glucose that will be taken up and metabolized.
This helps to restore energy balance, and takes pressure off the β-cells to
produce insulin because the amount of circulating glucose is decreased, thus
reducing insulin resistance (Sigal and Kenny 2004). Post-exercise, the muscle
and liver are more sensitive to insulin, glucose continues to be taken up into
the muscle and stored as glycogen and glucose taken up by the liver is
nonoxidatively metabolized (Hamilton et
al 1996). Regular exercise causes a number of physical adaptations within
the muscle that enables more efficient utilization of substrates for the
generation of ATP. Increased GLUT-4 protein expression occurs alongside
increased mitochondrial function, this helps to facilitate increased glucose
uptake into the muscle cell. The highest levels of GLUT-4 are normally found in
oxidative slow twitch muscle fibres. Interestingly, individuals with T2DM have
a distinct phenotype with a decreased amount of such fibres and reduced
concentration of GLUT-4 (Rockl et al
2008). Exercise training stimulates
protein synthesis which develops lean body mass, this lean tissue burns more
calories at rest than adipose tissue and helps to increase the basal metabolic
rate. Training also facilitates a shift in substrate utilization, the increased
mitochondrial and enzymatic activity enhances the muscles ability to extract
and oxidize glucose and NEFAs from the blood, as well as increase the
utilization of intramuscular triglycerides (Sigal and Kenny 2004). Moderate
exercise can increase fat oxidation approximately 10 fold due to increased
fatty acid mobilization and energy expenditure. Increased adipocyte
catecholamine sensitivity is the proposed reason for the enhanced capability to
mobilize NEFAs and reduce intramuscular triglyceride stores (Sigal and Kenny
2004).
Figure
2. Diagram representing different
signaling pathways for GLUT-4 translocation to facilitate glucose transport in
response to insulin and exercise (Rockl et
al 2008).
Role
of Exercise in Prevention of T2DM
There
is a substantial body of evidence in the diabetes research literature that
supports the value of exercise in the prevention of T2DM (Sigal et al 2006, Simpson et al 2003, Hansen et al
2010, Praet and Van Loon 2007). Exercise has proven to be equally as effective
in preventing the progression from IGT to T2DM when compared to a combination
of diet and exercise, and its beneficial effect on glycaemic control is
modulated independent of weight loss (Sigal et
al 2004). Current clinical recommendations declare that performing moderate
intensity exercise on at least 3 days of the week for a minimum of 30 minutes
per session can result in significant health benefits for patients with IFG and
T2DM (Sigal et al 2006). The benefits
of exercise can be greatly enhanced depending on the frequency, intensity,
type, and time spent exercising.
Frequency
Following
an acute bout of exercise, insulin sensitivity is enhanced for up to 72 hours.
Research indicates that regular exercise has a cumulative effect on improving
glycaemic control, with each successive bout of exercise further enhancing the
positive responsive adaptations (Praet and Van Loon 2007). The minimum
recommendations for exercise frequency is 3 days per week, with no more than 2
consecutive days between exercise bouts according to the American Diabetes
Association guidelines (American Diabetes Association 2007). Greater exercise
frequency as part of a long term lifestyle intervention has been shown to
improve body composition in obese individuals by facilitating greater adipose
tissue mass loss by creating an energy deficit, however, it has also been shown
that the long term benefits of exercise on glycaemic control may be lost within
6-14 days if exercise is discontinued (Hittel et al 2005).
Intensity
Recommendations
for continuous endurance training intensity varies between 40%-85% of VO2max
depending on what stage the patient is at in the lifestyle intervention (Hansen
et al 2010). After exercising at
intensities outlined above we get an increase in PGC-1α, this is
considered as a master regulator for metabolism and increases the capability of
the muscle to utilize glucose and fat (Canto and Auwerx 2009). For obese
individuals, lower intensity exercise is recommended in the early stages of the
intervention to assist in greater compliance to the training program. Low
intensity continuous endurance-type training has shown to be as effective as
high intensity continuous endurance-type training in improving glycaemic
control provided that the exercise bouts are of sufficient duration (Hansen et al 2010).
Muscle
glycogen plays a more important role in substrate metabolism as exercise
intensity is increased. High intensity exercise depletes muscle glycogen stores
to a greater degree and subsequent post-exercise glycogen synthesis is linked
with improvements in glucose tolerance and insulin sensitivity (Praet and Van
Loon 2007). In theory, when the acute
glucoregulatory effects of exercise are considered, high intensity exercise
should be more effective than low intensity. However when both intensities have
been compared, similar results were found in terms of loss of total-body
adipose tissue and enhanced glycaemic control (Schjerve et al 2008). The total amount of energy expended during the
exercise bout appears to be the most important factor for inducing changes in
glucose homeostasis, thus low intensity exercise should be performed for longer
durations than high intensity exercise (Praet and Van Loon 2007).
Type
Current
guidelines recommend the addition of resistance training alongside
endurance-type regimens. The addition of resistance training results in
enhanced glycaemic control for sufferers of T2DM (Hansen et al 2010). Resistance training increases energy expenditure and
produces sizable gains in muscle mass, thus improving whole-body blood glucose
disposal capacity (Praet and Van Loon 2007).
Resistance training improves bone density, balance, functional strength,
and increases the resting basal metabolic rate which can improve long-term
weight management and facilitate a more active and healthier lifestyle. Research
has shown significant improvements in insulin sensitivity when resistance and
endurance training is combined (77% increase) in comparison to endurance
training alone (20% increase) after 16 weeks (Sigal et al 2007). One of the main factors for increased incidence of
diabetes in older age is the loss of muscle mass, age-related sarcopenia can be
attenuated with resistance training, thus improving the metabolic profile of
older adults at risk of developing the disease (Hansen et al 2010). The ACSM
recommends 2-3 resistance training sessions per week, with 8-10 exercises that
recruit the major muscle groups. 1 set of 10-15 repetitions is advised for
beginners, with the aim of progressing to 3 sets of 8-10 repetitions over time
(Sigal et al 2004). Although one set
may be sufficient to promote strength gains, research has shown that 3 sets are
optimal for producing the metabolic benefits for T2DM (Hansen et al 2010).
Time
Currently,
there is a lack of information in the scientific literature that provides
guidelines on the optimal volume/duration for acute bouts of exercise (Praet
and Van Loon 2007). Rather, the
intensity of exercise appears to have a greater importance. A study by Sriwijitkamol
and colleagues (2007) found a greater decrease in blood plasma glucose levels
in patients with T2DM after cycling for 40 minutes at 70% VO2max, when
compared to a group that exercised at 50% VO2max. Recommendations
currently focus on the energy cost of each exercise bout with energy
expenditure in the region of 400-500 kcal deemed optimal regardless of the
duration of the session (Praet and Van Loon 2007).
Lifelong
participation in exercise is recommended to manage and prevent T2DM. Adherence
to extended exercise programs have resulted in significant improvements in
glycaemic control and considerable reductions in fat mass in obesity patients
with T2DM (Hansen et al 2010). These improvements result in enhanced quality
of life and life expectancy, as well as reductions in healthcare costs.
The
Future Role of Exercise
Several
recent studies have examined the effects of high-intensity intermittent
training (HIIT) in T2DM patients. The results from these studies have so far
been positive, Tjonna et al (2008) found
significant increases in insulin sensitivity after a 16 week HIIT intervention
in patients with IGT when compared to a continuous exercise intensity group. It
has been discovered that the HIIT provides a much greater upregulation of
PGC-1α, induces faster physiological adaptations in skeletal muscle, and
improvements in body composition (Hansen et
al 2010). This modality of training seems to provide greater benefits over
traditional methods and is an area that warrants additional research in
addition to future studies to provide a better understanding of the underlying
mechanisms that promote the upregulation of GLUT-4 and insulin signaling
features as a result of exercise. Muscle is now viewed as an endocrine hormone,
not only is its contractility affecting energy expenditure during exercise but
it is also releasing myokines which interact with other tissues in the body
such as the liver and adipose (Pedersen 2009). Knowledge and understanding of
these mechanisms can help clinicians and sports & exercise scientists to
develop optimal exercise routines to enhance insulin action in patients with
IGT and T2DM.
In
order to combat this disease, there is a need to design strategies to address
lifestyle choices on a large scale (Simpson et
al 2003). A community-wide approach is recommended with special emphasis
targeted at high risk groups such as pre-diabetic individuals. Education about
appropriate lifestyle choices should be implemented at an early age and a
structured program on lifestyle, exercise, and nutrition should form a
compulsory part of the school curriculum (Simpson et al 2003). Putting these measures in place can help combat this
largely preventable disease, improve quality of life, and reduce the economic
burden associated with its treatment.
