Benefit and risk of exercise on myocardial function in diabetes.
ABSTRACT Regular physical activity promotes cardiorespiratory fitness and has been considered a cornerstone for non-pharmacological treatment of more than 17 million Americans with diabetes mellitus. Physical exercise has been shown to positively affect certain cardiovascular risk factors such as insulin resistance, glucose metabolism, blood pressure and body fat composition, which are closely associated with diabetes and heart disease. With the increasingly sedentary life style in our society, routine daily exercise of moderate intensity is highly recommended to reduce cardiovascular risk, the leading cause of death in diabetic patients. Exercise produces many beneficial effects to the heart function such as reduced incidence of coronary heart disease, attenuated severity of diabetic cardiomyopathy, improved cardiac performance, cardiac reserve and autonomic regulation. Nevertheless, many diabetic patients do not appear to gain much benefit from exercise or may even be at risk of performing physical exercise. This review summarizes the benefit and risk of exercise on diabetic heart function, with a special emphasis on myocardial and autonomic function.
Article: Diabetic cardiomyopathy.[show abstract] [hide abstract]
ABSTRACT: The purpose of this article was to review the clinical and experimental features of diabetic cardiomyopathy, with particular relevance to the Black population. One hundred thirty-seven studies were identified, of which 57 were selected as references for this article. Diabetes is associated with the development of cardiomyopathy, independent of coronary atherosclerosis. Pathological studies show myocardial hypertrophy and fibrosis; microvascular pathology is also present, but all of these pathological findings have an uncertain relationship to myocardial failure. Hemodynamic findings of both congestive and restrictive cardiomyopathy have been described. Noninvasive studies revealed abnormal systolic and diastolic function in many diabetic subjects, particularly in the presence of diabetic complications and/or hypertension. Experimental studies have focused on the mildly diabetic dog and the severely diabetic rat. One year of diabetes in dogs resulted in decreased left ventricular compliance and increased interstitial connective tissue. Studies in the diabetic rat showed a marked slowing of contraction and relaxation. Chronic insulin therapy reversed the changes in the rat model. Combining hypertension with diabetes in the rat resulted in increased myocardial and coronary microvascular pathology and greater changes in isolated muscle function, electrophysiology, and contractile protein biochemistry. Many hypertensive diabetic rats died spontaneously, showing signs of congestive heart failure. Diabetic cardiomyopathy is a significant cause of heart failure in diabetic subjects and occurs more frequently in those with microvascular complications and/or hypertension. Clinical studies are needed to clarify the natural history of this disorder, focusing on the benefits of tight control of hyperglycemia and treatment of associated hypertension. Experimental studies will clarify the pathophysiology and contribute to improved therapy. The high prevalence of diabetes and hypertension in Blacks makes these considerations especially relevant to this population.Diabetes Care 12/1990; 13(11):1169-79. · 7.74 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: To determine whether diabetes-induced cardiac dysfunction is due to contractile dysfunction at the single-cell level, mechanical properties and Ca2+ transients were evaluated in ventricular myocytes isolated from diabetic rats. Rats were made diabetic by injection with streptozotocin and killed either 4-6 days or 8 wk after treatment. Shortening and relengthening (twitch) properties were evaluated in isolated myocytes with a high-resolution (120-Hz) video-based edge-detection system during electrical stimulation between 0.1 and 5 Hz. A separate cohort of myocytes was loaded with fura 2 to assess intracellular Ga2+ transients. Long-term (8-wk) but not short-term (4- to 6-day) diabetes depressed peak twitch amplitude. Diabetes markedly prolonged both the contraction and relaxation phases from both diabetic models. Additionally, 35% of the long-term diabetic myocytes could not pace at 5 Hz, and 48% of the short-term diabetic myocytes developed a hypercontracture at that frequency. Intracellular Ca2+ measurements showed slower Ca(2+)-transient decays in myocytes from short-term diabetic rats. These data demonstrate that contractile dysfunction seen in the diabetic heart is due, in part, to abnormalities of the myocyte. Furthermore, these abnormalities are present after only 4-6 days of diabetes, suggesting a rapid alteration in the processes regulating myocyte shortening and relengthening, which likely include impaired Ca2+ sequestration or extrusion.The American journal of physiology 02/1997; 272(1 Pt 2):H148-58. · 3.28 Impact Factor
Article: Diabetic cardiomyopathy.[show abstract] [hide abstract]
ABSTRACT: Prior to 1972, the increased cardiovascular morbidity and mortality that diabetics endure had been attributed to vascular disease. In 1972, Rubler et al. proposed the existence of a diabetic cardiomyopathy based on their expereince with four adult diabetic patients who suffered from congestive heart failure (CHF) in the absence of discernable coronary artery disease, valvular or congenital heart disease, hypertension, or alcoholism. Alternative explanations for CHF, such as anemia and vascular and renal disease in these four patients, gave rise to criticisms, but a wave of subsequent studies in the 1970s and 1980s provided credence to this new disease entity. This review of the studies done since 1972 appears to support the concept of a diabetic cardiomyopathy independent of atherosclerotic cardiovascular disease. The exact mechanism is still questionable, and several mechanisms have been proposed including small and microvascular disease, autonomic dysfunction, metabolic derangements, and interstitial fibrosis. However, the weight of evidence leans toward the development of fibrosis, possibly caused by the accumulation of a peroxidase acid schiff (PAS)-positive glycoprotein, leading to myocardial hypertrophy and diastolic dysfunction.Clinical Cardiology 01/1999; 21(12):885-7. · 1.83 Impact Factor
Pharmacological Research 48 (2003) 127–132
Benefit and risk of exercise on myocardial function in diabetes
Shiyan Li, Bruce Culver, Jun Ren∗
Division of Pharmaceutical Sciences and Graduate Neuroscience Program, University of Wyoming College of Health Sciences,
P.O. Box 3375, Laramie, WY 82071-3375, USA
Accepted 11 March 2003
Regular physical activity promotes cardiorespiratory fitness and has been considered a cornerstone for non-pharmacological treatment
of more than 17 million Americans with diabetes mellitus. Physical exercise has been shown to positively affect certain cardiovascular
risk factors such as insulin resistance, glucose metabolism, blood pressure and body fat composition, which are closely associated with
diabetes and heart disease. With the increasingly sedentary life style in our society, routine daily exercise of moderate intensity is highly
recommended to reduce cardiovascular risk, the leading cause of death in diabetic patients. Exercise produces many beneficial effects to
the heart function such as reduced incidence of coronary heart disease, attenuated severity of diabetic cardiomyopathy, improved cardiac
performance, cardiac reserve and autonomic regulation. Nevertheless, many diabetic patients do not appear to gain much benefit from
exercise or may even be at risk of performing physical exercise. This review summarizes the benefit and risk of exercise on diabetic heart
function, with a special emphasis on myocardial and autonomic function.
© 2003 Elsevier Science Ltd. All rights reserved.
Keywords: Diabetes mellitus; Myocardial contractility; Exercise; Benefit; Risk
Diabetes is caused by failure to maintain blood glucose
at a stable level in the face of the normal fluctuations of
supply and demand. Type 1 or insulin-dependent diabetes
mellitus, in which the insulin secretagogues in the pancreas
are damaged early in life, and the more insidious type 2
or non-insulin-dependent diabetes mellitus, where envi-
ronmental and dietary overload destroy the blood glucose
regulatory function, may both lead to severe complica-
tions such as cardiomyopathy, neuropathy, retinopathy and
nephropathy . It is predicted that the incidence of dia-
betes may be doubled over the next two decades largely due
to the sedentary lifestyles and an ever growing cluster of
pre-diabetic syndromes including syndrome X, obesity, and
insulin resistance [2–4]. All of these metabolic disturbances
are considered major risk factors for development of heart
dysfunction and congestive heart failure. Diabetic cardiomy-
opathy is a distinct disease entity independent of macro-
and micro-vascular diseases frequently seen in diabetic
patients. It is characterized by ventricular dysfunction and
abnormal intracellular Ca2+homeostasis and contributes
∗Corresponding author. Tel.: +1-307-766-6131; fax: +1-307-766-2953.
E-mail address: email@example.com (J. Ren).
directly to the myogenic cardiac dysfunctions in diabetic
individuals [5–8]. The increased risk of heart diseases,
especially diabetic cardiomyopathy, in diabetes warrants
stringent treatment of hyperglycemia and dyslipidemia.
The most commonly used therapeutic regimes in diabetic
patients with heart dysfunctions, such as low ejection frac-
tion, presently encompass angiotensin-converting enzyme
inhibitors, digoxin, diuretics, ?-blockers, and spironolac-
tone. Conversely, control of heart rate with ?-blockers or
Ca2+antagonists is essential if impaired diastolic func-
tion is predominant. In addition, the insulin-sensitizing
agents are recommended in treatment of diabetes over the
insulin-secretion-enhancing agents to avoid hyperinsuline-
mia and insulin resistance. In addition to pharmacological
interventions, primary care for patients with diabetes also
includes lifestyle modifications such as smoking cessation,
weight control, exercise and dietary restriction [9–11]. Re-
search has shown that routine exercise regimes reduce blood
glucose, blood pressure, body weight and body fat, and im-
proves lipid profiles [12–15]. However, the direct relation-
ship of exercise program and heart function in diabetes has
rarely been elucidated. This review will attempt to correlate
the benefit and risk of exercise on myocardial dysfunctions
in diabetes. We hope to provide some insight into under-
standing the complex etiology of diabetic cardiomyopathy
1043-6618/03/$ – see front matter © 2003 Elsevier Science Ltd. All rights reserved.
S. Li et al./Pharmacological Research 48 (2003) 127–132
and the suitability of applying exercise to improve cardiac
dysfunction in patients with diabetes.
2. Myocardial contractile dysfunction in diabetes
Diabetes has been shown to independently predispose the
heart to multiple abnormalities independent of atheroscle-
rosis, hypertension, coronary artery disease and valvular
disease [5,6,16,17]. Evidence from both human and experi-
mental animals has demonstrated the existence of a specific
diabetic cardiomyopathy independent of macrovascular
coronary artery complications [5,7]. Diabetic cardiomy-
opathy is believed to contribute to the high incidence of
cardiac dysfunction and mortality in both types of diabetes
[5,8]. Diastolic dysfunction is the most prominent mechan-
ical defect in diabetic cardiomyopathy and is characterized
by decreased compliance and slower rates of myocardial
relaxation [5–7]. Both systolic and diastolic dysfunctions
have been characterized as prolonged contraction and re-
laxation, reduced velocity of contraction and relaxation,
and depressed myocardial contractility in whole heart, tis-
sue, and isolated ventricular myocytes from both diabetic
patients and experimental animals [5–7,16]. Although the
pathogenesis of diabetic cardiomyopathy is not completely
understood, several speculations have been made regarding
the mechanism of action for diabetic cardiomyopathy, in-
cluding reduced energy production due to decreases in mito-
chondrial respiration and pyruvate dehydrogenase activity,
dysfunctional cardiac contractile and regulatory proteins
such as myosin isoform, myosin Ca2+-ATPase, as well as
impaired intracellular Ca2+homeostasis [17–20]. A shift
in myosin isozymes has been reported in diabetes from the
fast type (V1) to the slow type (V3), which may contribute
to the depressed velocity and prolonged duration of con-
traction [21,22]. Under normal conditions, the V1isoform
(two ? heavy chains) is predominant in cardiac muscles,
allowing the heart to contract with a high velocity, and the
highest ATPase activity. The V3isoform consists of two ?2
chains with slow contraction velocity and low ATPase activ-
ity. Besides the myosin filament, the troponin–tropomyosin
complex (TnTm) may be involved in diabetic mechanical
dysfunctions. Tropomyosin normally resides in the grooves
of the actin thin filaments and is anchored to troponin. The
troponin I subunit (TnI) is bound to the actin–tropomyosin
complex covering the binding sites of actin for myosin
heads, thus inhibiting interaction between actin and myosin.
A modification of the TnI subunit has been demonstrated in
diabetes and leads to reduced activity of cardiac actomyosin
Ca2+–Mg2+-ATPase. Since phosphorylation of TnI is im-
mediately associated with extracellular Ca2+-contractile
force relationship, alteration in TnI may directly contribute
to depressed myocardial contractility in diabetes .
It has been suggested that diabetic mechanical dysfunc-
tions may be underscored by the abnormal intracellular
transients associated with cardiac excitation–contraction
(E–C) coupling on a beat-to-beat basis, and this may be
responsible for the impaired relaxation [6,16,17]. The re-
duced cytosolic Ca2+clearing may be a result of impaired
and/or other Ca2+regulating proteins such as Na/Ca ex-
changer [17,20,24]. During relaxation, SERCA and Na/Ca
exchanger function to extrude cytosolic Ca2+, allowing the
myocardium to relax during diastolic phase . Decreased
activity in SERCA and/or Na/Ca exchanger would lead to a
chronic rise in [Ca2+]iand eventually a state of Ca2+over-
load. Insulin deficiency was reported to significantly reduce
the activity of Na/Ca exchanger in diabetic hearts .
Not surprisingly, impaired SERCA and Na/Ca exchanger
protein abundance or function may be partially restored
with normalization of glucose and insulin levels, or sup-
plementation of insulin analogue insulin-like growth factor
I (IGF-1) . Although these findings are not sufficient
to explain why cardiovascular abnormalities still persist in
diabetic patients even with insulin therapy, it suggested that
untreated diabetes (increased blood glucose and decreased
insulin) would inevitably impair the function of key cardiac
Ca2+regulatory proteins such as SERCA and Na/Ca ex-
changer leading to slowed intracellular Ca2+clearing and
intracellular Ca2+overload in diabetic hearts. In addition,
diabetes has been shown to depress the myofilament Ca2+
sensitivity [16,26], which also contributes to the reduced
cardiac contractility in diabetes.
3. Benefit of exercise on myocardial function
The most significant physiological adaptation of the heart
during exercise is manifested as increased delivery of blood
to peripheral vasculature to meet the enhanced demands of
the musculoskeletal and pulmonary systems [27–29]. This
is usually achieved with an increased cardiac output (CO)
through a combined increase of heart rate (HR), stroke vol-
ume (SV), and/or myocardial contractility [30,31]. Physical
exercise is often associated with an increased myocardial
chronotropic and inotropic response to the sympathetic sys-
tem (?-adrenergic response) as well as improved intrinsic
myogenic tone . Although the parasympathetic system
is known to participate in the tonic control of myocardium,
it is predominantly at rest. In this section, we will focus
on sympathetic and myogenic regulation of myocardial
function in diabetes during exercise.
Physical exercise is well known to improve glucose and
lipid metabolism and reduce insulin resistance . Re-
and duration improves cardiac performance and cardiac re-
serve in healthy non-diabetic individuals . The impact of
exercise on cardiac function in diabetes displays somewhat
similar patterns although patients with mild hyperglycemia
show a better response than those patients with severe
S. Li et al./Pharmacological Research 48 (2003) 127–132
hyperglycemia. Overall, there is a significant reduction of
cardiac morbidity and mortality in diabetic patients with
combined exercise and diet than with dietary control alone
. A significant lowering of cardiac contractile dysfunc-
tion and cardiac mortality was seen in insulin resistant and
type 2 diabetic patients with regular physical exercise of
moderate intensity . Although the mechanism of action
involved in the beneficial action of exercise in diabetic
cardiac dysfunction is not fully clear, major attention has
focused on the effect of exercise on the autonomic function
and cardiac contractile regulation of myogenic origin. It
was suggested that exercise increases the CO of both seden-
tary and diabetic animals at high, but not low, preload, thus
attenuating the depressed cardiac performance in diabetes
and severity of diabetic cardiomyopathy . It was also
reported that exercise improves cardiac pumping function,
lowers plasma triacylglycerol levels and increases carni-
tine content in diabetic hearts [36,37]. A close comparison
of diabetic-associated cardiac function at rest and during
exercise has provided some useful information regarding
the etiology of diabetic cardiomyopathy. As mentioned,
diabetes induces prolonged contraction and relaxation du-
ration at rest, associated with a significantly decreased CO
during “occasional” exercise. The most prominent cardiac
dysfunction under “occasional” exercise in diabetic patients
is decreased left ventricular ejection fraction (LVEF) .
The decreased (or unchanged in some reports) LVEF dur-
ing exercise cannot provide the cardiopulmonary system
with a sufficient supply of blood and oxygen to maintain
homeostatic conditions. In addition to decreased LVEF, left
ventricular diastolic dysfunctions have also been observed
during exercise . Digitized apexcardiography revealed
that early apexcardiographic relaxation time (EARTc) does
not differ significantly between normal and diabetic subjects
during resting condition. However, EARTcwas significantly
prolonged in diabetic patients following “occasional” ex-
ercise, indicating presence of diastolic dysfunction related
to exercise . As stated earlier, the reduced myocardial
function at rest and during exercise may be attributed to an
array of myocardial alterations such as a myosin isozyme
switch (V1–V3) and increased phosphorylation of cardiac
inhibitory protein TnI [22,23]. The inability to remove
intracellular Ca2+from the cytosolic space as a result of de-
pressed SERCA and Na/Ca exchanger function in diabetes
is also evident during exercise manifested as prolonged
early apexcardiographic relaxation time (EARTc) in dia-
betic hearts. Little effect has been reported regarding any
direct improvement of the messenger RNA, protein abun-
dance and function of these cardiac contractile proteins.
It is possible that exercise may improve cardiac function
through indirect actions on plasma lipid profiles and insulin
sensitivity. Both of these actions would improve cardiac
glucose utilization. This notion was supported by our pre-
liminary finding that exercise training and dietary supple-
mentation of fish oil or bezafibrate may effectively reverse
insulin resistance-induced cardiac contractile dysfunctions
in ventricular myocytes . Exercise has been shown to
attenuate the reduction in myocardial GLUT-4 transporters
 and up-regulate sarcolemmal GLUT-4 protein in dia-
betic rats . Exercise-associated improvement of insulin
sensitivity may play an essential role in this process since
the GLUT-4 depression and hemodynamic changes may
be reversed with insulin treatment. Insulin also enhances
LVEF during exercise in diabetics possibly due to improved
ventricular contractility under both exercise and insulin
treatment . In addition to the above mentioned possible
myogenic origins of beneficial actions of exercise on dia-
betic cardiac dysfunction, improvement of left ventricular
geometric characteristics due to exercise may have also
contributed to the action of exercise on diabetic hearts. Ex-
ercise has been shown to normalize the myocardial collagen
levels in diabetes .
One important aspect of exercise on cardiac function
in normal individuals has been associated with its ability
to enhance autonomic function. It is speculated that the
autonomic response may play a beneficial role of exercise
in diabetic cardiac dysfunction. Release of norepinephrine,
which is synthesized and stored in cardiac sympathetic
fibers, is considerably increased during exercise and leads
to improved cardiac performance in normal individuals. Ac-
tivation of the ?1 receptor by norepinephrine activates the
stimulatory G protein—Gs, and adenylate cyclase. The re-
sultant accumulation of cAMP leads to a rise of intracellular
Ca2+and enhanced cardiac contractility. Diabetic cardiomy-
opathy has been shown to display reduced adrenergic sensi-
tivity, with specific molecular alterations in the ?-adrenergic
receptor—G protein-adenylate cyclase signal transduction
system. The depressed catecholamine responsiveness and
impaired sympathetic nervous function may directly prompt
the onset of diabetic left ventricular dysfunction or diabetic
cardiomyopathy [46,47]. The diabetes-associated sympa-
thetic defect was further confirmed by the observation that
the ?-adrenergic agonist dobutamine fails to improve LVEF
in diabetic patients with exercise-induced left ventricular
dysfunction . In addition, plasma norepinephrine levels
are reported to be two to five-fold higher in diabetics than
those of normal subjects . It may be speculated that
prolonged exposure of catecholamine may down-regulate
the ?-adrenergic receptors, decreased sensitivity of adeny-
late cyclase and LVEF during exercise. These data suggest
that the potential beneficial effects of the ?-adrenergic
receptor-adenylate cyclase system on membranes from
ventricular tissue . While a decrease in the number of
?-adrenergic receptors would not allow the myocardium
to respond properly to norepinephrine during exercise, a
decrease in the activity of adenylate cyclase may be due
to modification of the ?-adrenergic receptor-linked adeny-
late cyclase system. Nevertheless, a recent report using
streptozotocin-induced diabetic rats indicated that exercise
improves diabetes-induced cardiac dysfunction and auto-
nomic dysregulation . Reduction in heart rates, seen in
sedentary diabetic subjects, has been attributed to changes
S. Li et al./Pharmacological Research 48 (2003) 127–132
in sinoatrial node. An increase in resting heart rates in
trained diabetic rats was observed, confirming the important
role of sinoatrial node changes in the heart rate in diabetes
. It may be speculated that the increase in resting heart
rate in trained diabetic rats may be the result of improved
intrinsic pacemaker regulation. It is suggested that exercise
does not modify parasympathetic tone in diabetes, although
a slight increase in vagal discharge was observed in trained
rats . Further investigation is still warranted to exam-
ine the impact of exercise on ?-adrenergic receptor-linked
adenylate cyclase system in diabetes.
4. Risk of exercise for myocardial function in diabetes
While exercise provides much benefit to diabetic pa-
tients, there are certain cardiovascular risks associated with
increased severity of diabetes [39,51]. Benefit of exercise
should be carefully weighed against the potential risk when
advising patients . In general, exercise may exaggerate
hyperglycemia or hypoglycemia through increased hepatic
glucose production or exercise-induced increased sensitivity
[53–55]. The potential for hyperglycemia may be magnified
in type 1 diabetes because of insufficient endogenous in-
sulin. Exercise may precipitate angina pectoris, myocardial
infarction, cardiac arrhythmias and sudden death if there
is pre-existing coronary artery disease. Several long-term
complications may be worsened by exercise. Diabetic au-
tonomic neuropathy, for example, may lead to arrhythmia
(prolonged QT intervals) in diabetic patients performing
exercise . In addition, diabetic patients with abnormal
exercise echocardiography are at much higher risk of car-
diac events such as cardiac death or nonfatal myocardial
infarction than those patients with normal exercise echocar-
diography , suggesting that exercise itself may be a
risk factor for certain diabetic populations. Another exam-
ple is that diabetic patients with altered exercise plasma
catecholamine response are associated with higher risk of
cardiac-cerebrovascular events. The altered exercise plasma
catecholamine response may be reflected as chronotropic
incompetence and lower plasma epinephrine response to
exercise due to abnormal sympathoadrenal function and
autonomic neuropathy in diabetes . Therefore, careful
screening of long-term complications of diabetes is essen-
tial for diabetics before any exercise program is initiated
[58,59]. For patients over 35 years of age, an exercise
stress test should be conducted to screen for ischemic car-
diac diseases that may not have been previously diagnosed
[60–62]. It appears that inappropriate or heavy exercise may
present more risk to older diabetic patients than younger
ones. Functional myocardial disease or diabetic cardiomy-
opathy is less severe or even absent in children and young
adolescents with diabetes, suggesting that manifestations
of the myopathic state may not be expected during the
pediatric years. Regular levels of habitual exercise are
expected more likely to affect aerobic fitness rather than
influences of the diabetic state itself in young diabetic
Physical inactivity is an independent predictor of all
cause mortality in diabetic patients . Regular exercise of
moderate intensity has been recommended as an important
component of the treatment and management for diabetes.
The benefit of exercise on diabetes lays not only on glu-
cose control but also on body weight gain, one of the most
powerful predictors for diabetes in genetically susceptible
individuals. Obesity is increasing dramatically and half of
the adults in developed countries are overweight. Consid-
ering little change in average caloric intake over the past
two decades, it is not difficult to conclude that this increase
in obesity is due to a reduction in physical activity. Thus,
regular exercise of moderate intensity is the key to the pre-
vention of weight gain and onset of type 2 diabetes. Since
exercise may present both benefit and risk to the diabetic
populations, only modest exercise, such as walking three
times a week, is recommended to achieve a cardioprotective
benefit . The exercise program of the Diabetes Preven-
tion Program aims at weekly expenditure of 2000calories
. In addition to diabetes, epidemiologic evidence also
suggests the benefit of physical activity in preventing car-
diovascular events in non-diabetic individuals. To unveil
the exact nature of the beneficial action of exercise on di-
abetic cardiac dysfunction, future studies should focus on
the mechanism of action of modest exercise on ventricular
contractile function such as the cardiac contractile protein
and autonomic nervous component such as on ?-adrenergic
receptor-linked adenylate cyclase system. These studies will
provide insight into the cellular pathophysiology of diabetes
cardiac dysfunction and in particular may establish novel
therapeutic avenues for the treatment and management of
cardiac dysfunction in diabetes, and possibly obesity.
The work in Dr. Ren’s laboratory has been supported
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