Abstract
Although the presence of cardiac dysfunction and cardiomyopathy in chronic diabetes has been recognized, the pathophysiology of diabetes-induced metabolic and subcellular changes as well as the therapeutic approaches for the prevention of diabetic cardiomyopathy are not fully understood. Cardiac dysfunction in chronic diabetes has been shown to be associated with Ca2+-handling abnormalities, increase in the availability of intracellular free Ca2+ and impaired sensitivity of myofibrils to Ca2+. Metabolic derangements, including depressed high-energy phosphate stores due to insulin deficiency or insulin resistance, as well as hormone imbalance and ultrastructural alterations, are also known to occur in the diabetic heart. It is pointed out that the activation of the sympathetic nervous system and renin–angiotensin system generates oxidative stress, which produces defects in subcellular organelles including sarcolemma, sarcoplasmic reticulum and myofibrils. Such subcellular remodeling plays a critical role in the pathogenesis of diabetic cardiomyopathy. In fact, blockade of the effects of neurohormonal systems has been observed to attenuate oxidative stress and occurrence of subcellular remodeling as well as metabolic abnormalities in the diabetic heart. This review is intended to describe some of the subcellular and metabolic changes that result in cardiac dysfunction in chronic diabetes. In addition, the therapeutic values of some pharmacological, metabolic and antioxidant interventions will be discussed. It is proposed that a combination therapy employing some metabolic agents or antioxidants with insulin may constitute an efficacious approach for the prevention of diabetic cardiomyopathy.
Highlights
Type 1 diabetes occurs as a result of insulin deficiency due to a defect in insulin-producing β-cells in the islets of Langerhans of the pancreas, while type 2 diabetes occurs as a consequence of insulin resistance/insensitivity of insulin receptors [1]
While this review has described the role of activated sympathetic nervous system (SNS) and renin–angiotensin system (RAS) neurohormonal systems in the pathogenesis of diabetic cardiomyopathy, cardiomyocytes are known to produce opioid peptides and receptors; β-endorphin is increased in the plasma of patients with congestive heart failure (CHF)
The complexity of diabetic cardiomyopathy is confounded by the diverse range of mechanisms that are involved in the pathogenesis of cardiac dysfunction in diabetes
Summary
Type 1 diabetes occurs as a result of insulin deficiency due to a defect in insulin-producing β-cells in the islets of Langerhans of the pancreas, while type 2 diabetes occurs as a consequence of insulin resistance/insensitivity of insulin receptors [1]. The depressed SL Na+-K+ ATPase, Na+-dependent Ca2+-uptake and ATP dependent Ca2+-uptake, as well as SR Ca2+-uptake and Ca2+-release activities and MF Ca2+-stimulated ATPase activity in diabetic hearts, were attenuated by propranolol treatment [6] These observations indicate that attenuation of subcellular remodeling in the diabetic heart by β-adrenoceptor blockade is associated with improved cardiac contractile activity. The depressed SL Na+-K+-ATPase, Na+-dependent Ca2+-uptake, and Ca2+-pump, as well as reduced SR Ca2+-release and Ca2+-pump activities and decreased MF Ca2+-ATPase activity in the diabetic heart, were improved (Table 4) These results demonstrate that the beneficial effects of RAS blockade in diabetes and improved cardiac performance are related to attenuation of SL, SR and MF defects in the heart. Blockade of SNS, RAS and platelet aggregation was shown to improve cardiac function and appears to superimpose the beneficial effects of insulin treatment alone
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