26.

Diabetes mellitus type 2 diabetes

Authors
Claes-Gran stenson, MD, PhD, Professor, Department of Endocrinology, Metabolism
and Dia betes, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
Kre Birkeland, MD, PhD, Professor, Department of Endocrinology, Aker University Hospital
and Faculty of Medicine, University of Oslo, Oslo, Norway
Jan Henriksson, MD, PhD, Professor, Department of Physiology and Pharmacology,
Karolinska Institutet, Stockholm, Sweden
Summary
Type 2 diabetes represents 8090 per cent of all diabetes and is a chronic disease charac-
terised by hyperglycemia and other metabolic disorders. The basis of treatment is meas-
ures that reduce insulin resistance, above all increased physical activity, weight loss in
the case of overweight, and stopping the use of tobacco. If these lifestyle measures are
not enough to properly control the disease, there are a number of different medications in
tablet form, and insulin.
Generally speaking, it can be said that, by leading to a decreased sensitivity to insulin,
physical inactivity is a significant risk factor for type 2 diabetes, and several studies have
shown that the development of type 2 diabetes can be prevented through exercise training
combined with dietary guidelines. Regular exercise for type 2 diabetes has a positive effect
on both insulin sensitivity and other risk factors for cardiovascular disease, for example,
blood lipid profile and blood pressure. This is of great importance since the risk for devel-
oping cardiovascular disease is three to four times higher in diabetes. Several studies also
report improved glucose control. It is recommended that the patient perform a minimum
of 30 minutes of medium intensity physical activity daily, such as a brisk walk, cycling or
similar activity adapted to his or her overall physical condition and lifestyle. Further health
effects and aerobic fitness can be achieved if this is combined with somewhat more inten-
sive exercise at least 23 times per week, such as a fitness class, tennis, swimming, skiing
or similar, depending on the individuals interests.
346 physical activity in the prevention and treatment of disease
Definition
Type 2 diabetes is a chronic disease characterised by hyperglycemia (elevated or abnor-
mally high blood sugar levels) and other metabolic disturbances, including metabolism
of lipids and haemostasis. The disease was earlier called adult-onset or non-insulin-
dependent diabetes, but these descriptions should no longer be used.
Prevalence/Incidence
Type 2 diabetes represents 8090 per cent of all diabetes. The total prevalence in the
Nordic countries is 45 per cent of the population over 20 years of age, but rises sharply
after the age of 5060 years. Approximately 20 per cent of people over the age of 70 years
are affected. In recent years, the disease has been shown in children with a genetic predis-
position and who also have other risk factors, for example, overweight and physical inac-
tivity. Globally, the incidence of type 2 diabetes is increasing dramatically, above all in
India, the Middle East, China, USA and parts of Latin America. The actual prevalence
is often unknown, as the disease can develop quite insidiously and not be detected until
a health check-up is performed. It has been estimated that the number of undiagnosed
patients with type 2 diabetes make up at least half or even the same number of patients
already known to have diabetes. In a small portion, approximately 5 per cent, of patients
earlier counted as type 2 diabetics, the genetic background has been established. These
people carry different types of mutations in transcription factors or glucokinase (Maturity
Onset Diabetes of the Young, MODY), which is inherited as autosomal dominant and
leads to diabetes in the early years (to be distinguished, however, from type 2 diabetes in
children with the risk factors mentioned above).
Cause
Hyperglycemia in type 2 diabetes most often develops due to insufficient insulin secretion
and reduced insulin sensitivity (insulin resistance). Insulin resistance presents, at least in
pronounced disease, both in the liver and in extrahepatic (outside the liver) tissues, princi-
pally in the skeletal muscle (1, 2). This leads to a pathologically increased glucose produc-
tion from the liver and reduced glucose uptake in the muscles. However, insulin resistance
cannot, on its own, lead to hyperglycemia/diabetes, but a concurrent defective secretion
of insulin from the beta cells in the islets of Langerhans is also required. Type 2 diabetes
develops in genetically predisposed individuals via a stage of reduced glucose tolerance.
Heredity is considered polygenous, but which genes are responsible for defects in insulin
secretion and/or insulin sensitivity is not yet fully established. Of the known candidate
genes associated to an increased risk for type 2 diabetes, most appear to have more signifi-
cance for insulin secretion than for insulin resistance (37).
26. diabetes mellitus type 2 diabetes 347
Risk factors
Most of the lifestyle factors that are known to increase the risk for type 2 diabetes reduce insulin
sensitivity (814). These include overweight, physical inactivity and the use of tobacco. There
is also evidence that a fat-rich and fibre-poor diet, as well as psychosocial stress, independent
of body weight, can lead to an increased risk for developing type 2 diabetes (10).
Pathophysiological mechanisms
The molecular mechanisms behind defective insulin secretion and insulin resistance
are still unclear. Insulin release is reduced primarily when stimulated with glucose, but
also when stimulated with other agents, such as certain amino acids. The beta cell defect
is likely primary, but some studies have shown that the defect may arise as a result of
exhaustion (high demand on secretion and concurrent insulin resistance). Even the toxic
effect of hyperglycemia (glucotoxicity) and dyslipidemia (lipotoxicity) can aggravate
beta cell function as well as insulin sensitivity, though these toxic effects can largely be
reversed by good metabolic control.
Symptoms and prognosis
In most patient with type 2 diabetes, the disease develops insidiously and with few symp-
toms. The diagnosis can be made at health check-ups or when more symptoms appear due
to higher blood glucose levels, for example, in the case of a serious infection or other concur-
rent disease. One can then observe increased urination and increased thirst, but rarely signifi-
cant weight loss. Other symptoms that should lead one to think of type 2 diabetes are skin
and urinary tract infections, polyneuropathy (disease of the peripheral nerves), impotence
and cardiovascular disease. As in other diabetes, there is a risk in type 2 diabetes for devel-
oping late complications in the eyes, nerves, kidneys and cardiovascular system. The risk of
myocardial infarction or stroke is 34 higher, and it is not uncommon that type 2 diabetes is
detected in patients with acute cardiovascular disease.
Diagnostics
Diabetes is defined as a fasting plasma glucose of 7.0 mmol/l or higher, symptoms of
diabetes and random plasma glucose measurements of over 11.0 mmol/l, or plasma glucose
over 11.0 mmol/l two hours after intake of 75 g glucose (oral glucose tolerance test).
Treatment
The basis of treatment on measures that reduce insulin resistance, mainly increased physical
activity (8, 9, 1220) and a fibre-rich diet containing a maximum of 30 per cent fat (primarily
mono- and polyunsaturated) and 5060 per cent complex carbohydrates. Any use of tobacco
should be stopped. If these lifestyle measures are not enough to properly control the disease,
there are a number of different kinds of oral medications and insulin (21).
348 physical activity in the prevention and treatment of disease
Metformin is the drug of choice, the main effect of which is the reduction of glucose
production in the liver, while sulfonylureas or glinides are used to stimulate insulin secre-
tion. Glitazones (thiazolidinediones) can be used in combination with either metformin or
insulin-stimulating drugs to increase insulin sensitivity, above all in muscle. Newer drugs
are analogues to the intestinal hormone GLP-1 (glucagon-like peptide), such as exenatide,
or enzyme inhibitors that increase the endogenous level of GLP-1, such as sitagliptin.
These drugs improve plasma glucose levels by, among other things, increasing the endog-
enous insulin secretion and inhibiting glucagon secretion. Acarbose inhibits the break-
down of disaccharides in the intestine. Type 2 diabetes is a progressive disease, however,
and after 510 years of treatment a large majority of patients fail on these peroral drugs.
Insulin treatment can then be required in order to maintain acceptable control, especially
if weight loss occurs. Today, insulin treatment is most often given in combination, for
example, with metformin. Primary insulin treatment can be necessary if the patient with
type 2 diabetes has high blood glucose levels at onset. In many cases a transition to peroral
therapy can occur later, however.
Effects of physical activity
Effect of acute exercise
In healthy individuals, physical exercise does not normally lead to changes in the blood
sugar concentration, even if maximal exertion can lead to increased blood sugar levels. This
generally also applies to type 2 diabetics with only dietary treatment, and it is unusual that
physical exercise leads to hypoglycemia in this patient group. These individuals therefore
do not normally need to think about eating more in connection with an exercise session, as
long as the physical exercise is not strenuous or long-lasting (e.g. a marathon race) (22). In
people with type 2 diabetes who receive insulin treatment, sulfonylurea drugs or glinides,
however, moderate to strenuous exercise leads to a fall in blood sugar concentration during
the exertion itself, a change that can remain up 12 hours after the exercise is finished. In the
course following very strenuous exercise, on the other hand, hyperglycemia can arise due to
increased plasma hormone levels, which stimulate the livers glucose production, together
with a reduction in the sugar uptake of the skeletal muscle post-exercise (23, 24).
Effects of regular exercise training
Regular exercise training in type 2 diabetics leads to an increase in the insulin sensitivity
of the tissues even at rest. An increased insulin sensitivity with training is also seen in
non-diabetics, but is of particular importance in type 2 diabetics and other patient groups
that normally already have a reduced insulin sensitivity at rest (12, 13, 1520, 25). It can
generally be said that, by leading to a lower sensitivity to insulin, physical inactivity is a
risk factor for type 2 diabetes, and several studies have shown that the development of type
2 diabetes can be prevented through exercise training.
26. diabetes mellitus type 2 diabetes 349
An interesting finding is that there is a reversed relationship between the amount of exer-
cise training and the risk of developing type 2 diabetes (10). Because type 2 diabetes is
associated with a 34 times higher risk for myocardial infarction and stroke, it is also
important that exercise training in this patient group has an impact on the risk factors for
heart disease, in addition to through the increased insulin sensitivity, also through leading
to an improved blood lipid profile and lower blood pressure (1619, 22, 26). An inter-
esting question is also whether blood sugar control is affected by exercise training in type
2 diabetics, since good blood sugar control reduces serious late complications in diabetes.
The research data in this area was negative for a long time, but recent studies have shown
that improved blood sugar control can be achieved with exercise training, especially for
younger age groups (27). A recently published study, in which non-insulin-treated type 2
diabetics (3970 years) were randomly assigned to endurance training, strength training,
combined training or to a control group without training, for 6 months, showed improved
blood sugar control, measured as glucosylated haemoglobin (HbA1c), in all training
groups. Significant best outcomes were shown in the sample group where fitness and
strength training were combined (28). In a randomised study, researchers were able to
show that lifestyle treatment (physical activity 23 times per week and dietary counseling)
were as effective at reducing HbA1c in a group of tablet-treated type 2 diabetics with poor
blood sugar control as starting insulin treatment (29).
Indications
Primary prevention
A number of randomised prospective studies and epidemiological observation studies
suggest good primary prevention effect from physical activity in individuals with reduced
glucose tolerance (1114, 3033). In some of these studies, regular exercise was combined
with weight loss (approx. 5%) (30, 31), whereas other large prospective studies have
shown a diabetes-preventive effect with physical activity as the only intervention (3234).
An example of the latter that can be noted is the study in the Chinese city of Da Qing (32),
in which 577 individuals with impaired glucose tolerance were divided into four groups,
among them a group with only exercise training as treatment. After 6 years, 68 per cent of
the individuals in the untreated control group had developed type 2 diabetes, compared to
only 41 per cent in the exercise group.
Secondary prevention
Regular physical activity is an important part of the treatment of type 2 diabetes (12, 13,
1620, 34). By contributing to good metabolic control (see above), it is likely that also the
development of late diabetic complications can be reduced.
350 physical activity in the prevention and treatment of disease
Prescription
Medium intensity physical activity, a minimum of 30 minutes per day of brisk walking,
cycling or similar activity, adapted to the individuals overall physical condition and life-
style. It is important to include warm-up and cool-down components of a lower intensity.
Further health and aerobic fitness effects can be achieved if this is combined with some-
what more intensive exercise at least 23 times per week, for example, a fitness class,
tennis, swimming, or skiing. Strength training is also recommended (Table 1). If cardio-
vascular symptoms are present the strength training should be less strenuos than shown in
the table, for example 1215 repetitions instead of recommended 812. In the case of eye
symptoms, even lighter weights should be used, for example,1520 repetitions of each
exercise. In order to avoid a rise in blood pressure, lifts should be done on exhalation
and the muscles relaxed during inhalation. For aerobic fitness and strength training, each
session should begin with a warm-up and end with a cool-down period of 510 minutes
each, including careful stretching of tight muscles and soft tissues.
Physical activity aimed at weight loss should be combined with a reduced calorie
intake. Hypoglycemia seldom occurs in connection with exercise and extra intake of
carbohydrates is therefore not necessary. Patients receiving insulin treatment or taking
insulin-stimulating peroral drugs may become hypoglycemic, however, especially if they
do not have pronounced insulin resistance (hypoglycemia in connection with physical
activity is also discussed under the heading of Effect of acute exercise in this chapter and
the chapter on type 1 diabetes).
Table 1. General recommendations for physical activity in type 2 diabetes mellitus (35).
Type of training Examples of activities Frequency Intensity Duration
Basic activity Walking, climbing stairs,
gardening. It is also desir-
able to increase standing/
walking time at work and
at home.
Daily So talking is still
possible, 3050%
of maximal oxygen
uptake;
1213 acc. to Borgs
scale.
> 30 min.
Aerobic tness
training
Nordic walking, jogging,
cycling, swimming, skiing,
skating, tness class/aero-
bics/dance, ball sports,
rowing.
35 times/
week
Until out of breath
Begin slowly and
gradually increase to
4070% of maximal
oxygen uptake;
1316 acc. to Borgs
scale*.
2060 min.
Strength training Movements using the body
as resistance, resistance
bands, weights, weight/
resistance equipment.
23 days/week Until or near muscu-
lar exhaustion for
each exercise**.
810 exercises,
with 812 reps
of each exercise
* Level of exertion may need to be reduced in the case of retinal, renal or cardiovascular complications as well as autonomic
dysfunction.
** Replace with easier exercises in the case of retinal, renal or cardiovascular complications.
26. diabetes mellitus type 2 diabetes 351
Functional mechanisms
Even though it is unusual for physical exercise to lead to hypoglycemia in people with
type 2 diabetes, the blood sugar concentration changes in connection with exercise more
often in type 2 diabetics than in non-diabetics. This has to do with the marked increase
in sugar uptake for the skeletal muscle during exertion due to a non-insulin-dependent
increased permeability of sugar to the muscle cells. In healthy non-diabetic individuals,
the increased sugar uptake of the skeletal muscle is compensated for during exertion by an
increased release of glucose from the liver due to an increase in the hormone glucagon as a
result of the exertion, while insulin levels fall. In people with type 2 diabetes, this compen-
sation is sometimes not sufficient and leads to lower blood sugar, possibly due to the fact
that the insulin concentration in the blood is often elevated in these people, which can
result in insufficient release of glucose from the liver (23, 24). The increased blood sugar
concentration seen in type 2 diabetics in the course following a vigourous exercise session
is considered to be connected to remaining high concentrations of so-called counter-regu-
lating hormones post-exercise (24).
The increased insulin sensitivity with regular exercise can be explained by changes at
different levels, for example, a changed body composition, with less fat and more muscle,
and cellular changes in the skeletal muscle, such as increased concentrations of glucose
transporter proteins and glycogen synthase (13, 25).
Functional tests/Need for health check-ups
In some cases, especially in older patients or in the case of long diabetes duration, it is
appropriate to conduct a stress test or other examination to assess heart status. The pres-
ence of peripheral neuropathy, impaired sensation, impaired joint function, eye complica-
tions (proliferative retinopathy) and kidney disease should also be assessed. The latter are
necessary because elevated blood pressure during activity may aggravate eye problems
and the development of kidney disease. And finally, one should examine the feet with
respect to loss of feeling, uneven loading, pressure sores and corns and calluses, as well as
the possible presence of sores.
Interactions with drug therapy
Physical activity increases both insulin sensitivity and insulin-independent glucose uptake
in muscle, and thus amplifies the insulin effect. This can be of practical importance in
certain patients receiving insulin treatment or insulin-stimulating peroral drugs.
352 physical activity in the prevention and treatment of disease
Contraindications
Relative
Caution with concurrent heart disease. In the case of peripheral neuropathy there is a risk
for injuries to the feet and joints. In the case of eye complications (proliferative retin-
opathy) there is a risk for exacerbation of eye status (uncommon). In the case of autonomic
neuropathy, physical activity that is too intensive can be associated with risks (hypotension
and lack of early warning signs for cardiac ischaemia). In the case of kidney disease, high
blood pressure (systolic pressure of 180200 mmHg) can aggravate the development of
the disease.
26. diabetes mellitus type 2 diabetes 353
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