REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
78
VOLUME 11 NUMBER 2 • JUNE 2014
and contains mitochondria, switches to a glycolytic fibre with less
vascularity and mitochondria. As exercise can improve oxidative
capacity, increase mitochondrial content,
75
and also increase muscle
perfusion,
31,32,34,45,76
the relationship between muscle perfusion, fibre
type and mitochondrial function needs to be clarified.
Exercise training may or may not have effects on the basal
metabolic rate. In older adults, 26 weeks of training increased
resting energy expenditure and also improved lipid oxidation rates.
77
Habitually active women were also found to have a higher resting
metabolic rate than matched sedentary controls, associated with
lower body fat levels.
78
However, there are a variety of studies that
show no effect of exercise intervention on basal metabolic rate,
such as one that used a 26-week training programme investigating
a mix of aerobic and resistance training.
79
These individuals were
previously sedentary and had a history of type 2 diabetes. Many
aerobic training studies fail to show an improvement in resting
metabolic rate, and Jennings
et al
.
79
note that resistance training
intensity or frequency may increase fat-free mass, which is the
primary cause of resting metabolic rate changes.
80
Therefore, the
lack of improvement in basal metabolic rate may be due to no
significant change in fat-free mass
79
or the reduced exercise capacity
of diabetic patients.
2
Treating metabolic disease
Aside from improvements in endothelial function, exercise can also
affect metabolism, and this can be exploited in metabolic disease
such as diabetes. Systemic vascular improvement can also improve
insulin sensitivity,
81
so targeting the endothelium in diabetes is a valid
option for treating metabolic disease.
82
The relationship between
vascular action and metabolism has been previously reviewed,
83
and
impaired vascular function has been implicated as the link between
obesity and diabetes.
84
Essentially, without appropriate blood flow,
distribution of blood through tissues, or transport from the vessels,
metabolic function is limited due to reduced nutrient and hormone
availability.
Exercise training improves insulin sensitivity,
54
and while this
can be due to an increase in insulin-specific glucose transporters
after exercise,
85
blood flow distribution changes may also indirectly
improve metabolism. In rodent models of obesity that show a
failure of insulin to increase muscle perfusion, muscle contraction
can still cause capillary recruitment and glucose uptake.
42
Insulin
and exercise have an additive effect on glucose uptake in muscle,
and the authors discuss the potential contribution of blood flow
and capillary surface area to their results.
86
In obese patients, the
defect in insulin-mediated skeletal muscle perfusion was restored
by exercise, yet cellular insulin resistance was still evident.
87
Therefore while exercise does increase the effect of insulin on
glucose metabolism in both lean and obese individuals, it does not
normalise the cellular deficit due to obesity. The increased insulin-
mediated glucose uptake observed with exercise training is likely
due to improved haemodynamic effects in muscle.
76
Complications
Insulin resistance per se may underlie the development of other
aspects of the metabolic syndrome
81
and many of these may have
a vascular basis. Targeting endothelial dysfunction is therefore a
viable treatment for preventing vascular complications associated
with diabetes.
70
The vascular component of exercise may well
be linked to the reduction of diabetic complications, such as
retinopathy, peripheral neuropathy and nephropathy, as there is a
vascular basis to many of these complications. The endothelium
has been implicated in diabetic nephropathy,
88
and the blood
vessels formed in response to reduced perfusion in retinopathy
show abnormal structure and function.
89
Endothelial dysfunction
is evident in hypertension and cardiovascular disease, and is also
noted in many cardiovascular risk factors, including abnormal
blood lipid levels, and hyperglycaemia. Treatment of those risk
factors typically restores endothelial function. Therefore systemic
vascular protection has been proposed as a treatment for type 2
diabetes that would prevent complications, but also improve insulin
sensitivity.
81
Physical exercise is anti-atherogenic,
90
but also confers
general vascular protection, and as such could prevent many of the
complications associated with diabetes.
Negative or neutral outcomes of exercise
Lifestyle interventions such as diet and exercise are the first
recommendation for treatment of diabetes and obesity, yet drug
treatment is a very common therapy. While diabetic patients have
defects in exercise capacity,
2
this can be improved by either exercise
training or agents that improve insulin sensitivity. Certain hormones
can be upregulated in metabolic disease, such as endothelin-1 in
hypertension, and excessive levels of endothelin-1 can reduce
aerobic capacity of muscle and impair metabolism,
91
most likely
through impaired blood flow. Investigations are on-going into
certain drugs that are designed to mimic exercise. For example,
sildenafil
92
and AICAR
93
have been shown to increase peripheral
microcirculation. However, there can be adverse effects of various
drugs in combination with exercise. For example, rosiglitazone
usage may improve exercise capacity but may contribute to heart
failure.
94
The Look AHEAD study shows diet and exercise, as part of an
intensive lifestyle intervention, had no significant effect on lowering
cardiovascular events in overweight or obese individuals, which
could suggest that exercise has no long-term cardiovascular benefit,
4
and complete remission of type 2 diabetes is rare.
95
However, the
control group in this study was assigned to diabetes support and
education, and no measure of physical activity or dietary changes
was performed in this group. Therefore while 6 kg weight loss was
achieved by diet and exercise after nearly 10 years, the control group
also showed weight loss of 4 kg.
4
The use of drugs in the Look
AHEAD study may also explain the apparent lack of improvement
in cardiovascular outcomes with lifestyle intervention,
4
based on
potential drug interactions listed above. However, the same study
did show partial remission of type 2 diabetes,
95
and noted that
improvements in glycaemic control by exercise were dependent
on the blood glucose level prior to beginning the intervention.
96
A similar study investigated lifestyle intervention in overweight
people with impaired glucose tolerance, and similarly showed no
effect of intervention to decrease cardiovascular morbidity after
10 years. However this study showed a decrease in the incidence
of type 2 diabetes in the lifestyle-intervention group, therefore
exercise and diet were able to reduce type 2 diabetes incidence.
97
Therefore, exercise should be an early intervention to prevent type 2
diabetes and obesity, as it is more effective after a shorter duration
of diabetes,
96
and can prevent at-risk individuals from progressing
to type 2 diabetes.
97
Further, short-term exercise interventions
have caused weight loss, restored insulin sensitivity, as well as
improved cardiometabolic risk factors.
98
Therefore, exercise is an
