diabetes mellitus often leads to heart failure ( hf ) , even in the absence of any other risk factors such as coronary artery disease or hypertension , suggesting that diabetes itself causes a specific form of cardiomyopathic state .
diabetes causes myocardial structural remodeling characterized by myocyte hypertrophy , interstitial fibrosis , and apoptosis , which increases cardiac muscle stiffness and may contribute to diastolic dysfunction .
diastolic dysfunction has been regarded as a hemodynamic hallmark seen in diabetes and ultimately contributes to the development of hf .
previous clinical studies have shown that patients with diabetes have a worse outcome after mi than patients without diabetes despite similar left ventricular ( lv ) ejection fractions and coronary patency rates .
the features of diabetic heart disease have been well identified , however , its pathogenesis and , in particular , the mechanisms underlying myocardial remodeling have not been fully elucidated .
the excess production of reactive oxygen species ( ros ) , superoxide anion ( o2 ) , h2o2 , and hydroxyl radical ( oh ) , resulting in oxidative stress , is widely considered to be a cause of target organ damage such as the heart , kidney , and skeletal muscle , in diabetes . therefore , oxidative stress may contribute to the development of cardiac and skeletal muscle dysfunction in diabetes .
diabetes mellitus causes both diastolic and systolic cardiac dysfunction , but an impairment of diastolic function usually occurs before systolic dysfunction develops . the impairment of diastolic function despite normal systolic function is thought to result from an increased myocardial stiffness .
a growing body of evidence suggests that the production of ros is increased in the diabetic heart .
the first line of defense against ros - mediated cardiac injury comprises several antioxidant enzymes including superoxide dismutase ( sod ) , catalase , and glutathione peroxidase ( gshpx ) .
it not only scavenges h2o2 but also prevents the formation of other more toxic radicals such as oh .
furthermore , it is present in relatively high amounts within the heart , especially in the cytosolic and mitochondrial compartments
. these lines of evidence imply the primary importance of gshpx as a defense mechanism within the heart .
moreover , gshpx is expected to exert greater protective effects against oxidative damage than sod because greater dismutation of o2 by sod may result in an increase of h2o2 .
therefore , compared with sod or catalase , gshpx is thought to be more effective in protecting cells , tissues , and organs against oxidative damage .
in fact , the mice with gshpx gene overexpression were more resistant to myocardial oxidative stress as well as remodeling and failure after mi . in the diabetic heart ,
the reduction of myocardial oxidative stress by gshpx overexpression was associated with the attenuation of diastolic dysfunction , myocyte hypertrophy , and interstitial fibrosis .
these findings are consistent with previous studies demonstrating that ros are involved in the structural alterations of the extracellular matrix collagens .
the decline in myocardial fibrosis by gshpx overexpression may contribute to the physiological improvement of diastolic properties .
first , oxidative stress is involved in cardiac myocyte hypertrophy and apoptosis . a subtle increase in ros caused by partial inhibition of sod results in hypertrophy and apoptosis in isolated cardiac myocytes , both of which
specifically , the incidence of apoptosis is increased in the diabetic heart , which may cause loss of myocytes , compensatory hypertrophy of residual myocytes , and interstitial infibrosis .
we have demonstrated that mmp-2 activation plays an important role in the pathophysiology of cardiac remodeling .
on the basis of these findings , increased ros may contribute to the activation of mmp and thus to the development of interstitial fibrosis in diabetes .
third , a possible role for growth factors in diabetes - related end - organ complications is increasingly being recognized .
transforming growth factor ( tgf)- and connective tissue growth factor ( ctgf ) can induce the production of collagen and fibronectin from cardiac fibroblasts and myocytes , and increased expression of both factors contributes to the development and progression of cardiac remodeling in diabetes .
previous clinical findings demonstrated that patients with diabetes have a worse outcome after mi than that of patients without diabetes despite similar coronary patency rate and baseline lv ejection fraction .
furthermore , in the clinical study of patients with hf , diabetes reduced long - term survival independent of the etiology of hf and baseline lv ejection fraction .
the poor outomes in patients with diabetes have been shown to be related with the progression of hf .
streptozotocin induces diabetes in rodents by chemical destruction of insulin - producing -cells of the pancreatic islets , which thus models type 1 diabetes resulted from an auto immune - mediated loss of -cell mass .
hyperglycemia induced by streptozotocin exaggerates lv remodeling and failure after mi . in contrast , type 2 diabetes is typically preceded by obesity and associated metabolic abnormalities such as insulin resistance and dyslipidemia .
type 2 diabetes can be modeled by feeding a high - fat diet ( hfd ) in mice .
a hfd leads to insulin resistance , impaired glucose tolerance , an increase in body fat and dyslipidemia , and eventually fasting hyperglycemia .
we demonstrated that hfd induced type 2 diabetes characterized by insulin resistance and obesity in mice and exacerbated lv remodeling and failure after mi .
similarly , in goto kakizaki rats , a nonobese type 2 diabetes model , the progression of hf was accelerated after mi .
therefore , either type 1 or type 2 diabetes exaggerates post - mi lv remodeling and failure . the production of ros is increased in post - mi hearts , and pharmacological and genetic interventions to scavenge ros can ameliorate this disease process .
importantly , the activation of nad(p)h oxidase enhances oxidative stress and plays an important role also in the progression of post - mi diabetic heart as in other diabetic complications .
in patients with type 2 diabetes , the exercise capacity is limited and the lower exercise capacity is a significant independent predictor for mortality .
exercise intolerance is generally believed to be due to the abnormalities in the energy metabolism in skeletal muscle . moreover , mitochondrial fatty acid -oxidation and mitochondrial respiration were impaired in skeletal muscle from patients with type 2 diabetes .
these results suggest that diabetes may adversely affect mitochondrial function in skeletal muscle and lead to exercise intolerance .
systemic oxidative stress has been reported to be increased in type 2 diabetes . moreover ,
the mitochondrial structure and function were impaired in skeletal muscle from hfd - fed rodents with the altered oxidative stress markers .
therefore , increased oxidative stress in skeletal muscle may impair mitochondrial function and limit the exercise capacity in type 2 diabetes .
we demonstrated that the exercise capacity was limited in the diabetic mice induced by hfd feeding .
coincident with these alterations , mitochondrial respiratory activity , electron transport chain ( etc ) complex i and iii activities and skeletal muscle mitochondrial content were decreased in the hfd mice .
these findings are supported by the previous studies in patients with insulin resistance or type 2 diabetes , in which mitochondrial atp production and state 3 respiration were decreased in skeletal muscle . moreover ,
mitochondrial oxidative phosphorylation genes including ubiquinol cytochrome c reductase binding protein , a subunit of complex iii , were downregulated in skeletal muscle from patients with diabetes , and their expression levels were positively correlated with peak vo2 .
accordingly , the metabolic abnormalities in the mitochondria from skeletal muscle can well explain a decrease in the exercise capacity and peak vo2 in the diabetic mice .
importantly , chronic administration of apocynin in the hfd mice significantly ameliorated the limited exercise capacity as well as mitochondrial dysfunction in skeletal muscle without affecting glucose metabolism or body fat .
therefore , increased oxidative stress causes mitochondrial dysfunction in skeletal muscle and contribute to exercise intolerance in diabetes .
these findings are in agreement with our previous study that the exercise capacity was reduced in conditions in which o2 was increased in heterozygous manganese sod gene knockout mice .
the exercise capacity has been reported to be decreased also in rats fed vitamin e - deficient diets .
therefore , oxidative stress and mitochondrial dysfunction in skeletal muscle play a crucial role not only in the development of insulin resistance but also exercise intolerance in type 2 diabetes .
the decrease of mitochondrial etc complex i and iii activities can potentially be explained by direct oxidative damage to mitochondrial complexes .
mitochondria can be the primary target for oxidative damage when ros production exceeds the capacity of the endogenous ros scavenging system .
in addition , oxidative damage to mitochondrial dna can also result in the decrease in etc complex activities .
an explosive increase of patients with type 2 diabetes is a growing medical as well as public health problem in industrialized countries .
therefore , the development of novel therapeutic approaches for diabetes is an important goal for further investigation .
the first line in the prevention and treatment of diabetes is the lifestyle modification including diet and physical exercise .
exercise training can increase mitochondrial oxidative capacity in skeletal muscle and delay or prevent diabetes by increasing insulin sensitivity .
however , the limited exercise capacity might prevent the completion of proper exercise in patients with type 2 diabetes .
therefore , therapies designed to regulate oxidative stress and maintain mitochondrial function in skeletal muscle are expected to increase the exercise capacity , which may be beneficial in the treatment of diabetes and the prevention of cardiovascular diseases .
to improve the outcomes of patients with hf , the development of therapeutic strategies based on a novel insight into the pathophysiology of cardiac and skeletal muscle remodeling is critically needed .
therapies designed to interfere with oxidative stress could be beneficial to prevent not only diabetic heart disease but also skeletal muscle dysfunction in diabetes .
 diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease . 
 it also causes skeletal muscle dysfunction , which is responsible for reduced exercise capacity commonly seen in heart failure . 
 the underlying pathogenesis is partially understood . 
 several factors may contribute to the development of cardiac and skeletal muscle dysfunction in heart failure and diabetes mellitus . 
 based on the findings in animal models , this review discusses the role of oxidative stress that may be involved in the development and progression of cardiac and skeletal dysfunction associated with diabetes . 
Introduction
Diabetic Heart
Post-MI Diabetic Heart
Skeletal Muscle Dysfunction in Diabetes Mellitus
Conclusion