Cardiomyopathy (CM) is the disease of the heart in which the muscle of the heart, the myocardium is damaged. The damage may be due to various causes like hypertension, diabetes mellitus. However, the people with CM may suffer from arrhythmia and sudden cardiac death. Patients with diabetes mellitus often develop artherosclerosis and hypertension both of which are major contributors to heart disease. However, cardiomyopathy can develop independent of elevated blood pressure or coronary artery disease, a process termed ‘diabetic cardiomyopathy’. This disorder is a complex diabetes associated process characterised by significant changes in the physiology structure and mechanical function of the heart. The various mechanisms and molecular events involved in the pathogenesis of diabetic cardiomyopathy are discussed below:

Molecular mechanisms
Diabetes mellitus is characterised by hyperglycaemia due to either insulin deficiency or insulin resistance. The concept of diabetic cardiomyopathy is based on the notion is that diabetes mellitus is a key factor in eliciting changes in the cellular and molecular levels of the myocytis.The hormone insulin is important in  maintaining the carbohydrate and lipid metabolism and thereby the normal glucose levels throughout the body. In diabetes mellitus, insulin deficiency/ resistance alters the metabolism contributing to diabetic cardiomyopathy.

Hyperglycemia & glucotoxicity
Hyperglycaemia is caused because of decreased glucose clearance and continuous hepatic gluconeogenesis. Chronic hyperglycaemia leads to glucotoxicity which causes cardiac injury through direct and indirect effects on cardiomyocytes, cardiac fibroblasts and endothelial cells. It promotes over production of reactive oxygen species through electron transport chain (ETC) and therefore, causes alteration in cardiac structure and function.

Hyperlipidemia & lipotoxicity
Due to hyperglycaemia, excess glucose is directed towards lipid synthesis. This enhanced lipid synthesis in hepatocytes and increased lipolysis in cells due to decreased carbohydrates in adipocytes causes an increase in the circulating fatty acid and tri glycerides in patients with diabetes. Also, insulin facilitates fatty acid transport into cardiac myocytes. Thus, circulating lipids in hyperinsulniemia together cause fatty acid delivery to cardiac cells which rapidly utilize it. Now, if fatty acid delivery exceeds the oxidative capacity of the cells, fatty acid accumulates leading to cardiac lipotoxicity.

Mechanism that contributing to cardiac lipotoxicity are:
Reactive Oxidative Species (ROS): ROS production occurs due to high rates of fatty acid oxidation which are removed by antioxidant enzymes. But cardiomyocytes damage and death by apoptosis occurs if ROS generation exceeds its degradation leading to accumulation.

Impaired contractility: Intracellular fatty acid accumulation can trigger opening of potassium-ATP channel leading to action potential shortening which reduces entry of calcium leading to reduced sarcoplasmic reticular calcium stores and contractility.

Hyperinsulinemia, insulin resistance & altered substrate metabolism
Studies have indicated an association between hyperinsulinemia and development of cardiac hypertrophy (enlarged heart). The cascade activated by insulin along with neurohormonal growth agonists EGF-1 and angiotensin-2 activate both ERK and AKT, which are involved in cell growth and protein synthesis. An increased level of AKT is associated with physiological hypertrophy and that of ERK with pathological hypertrophy. Thus, chronic hyperinsulinemia can lead to increased AKT-1 by either sympathetic stimulation or angiotensin-2. Insulin resistance is defined as diminished insulin dependent stimulation of myocardial glucose uptake including accumulation of fatty acid which impairs insulin mediated glucose uptake.

Dysregulation of RAS, adipokines
Renin-angiotensin system (RAS) has been found to have effects on cardiac cells. Angiotensin-2 has widespread effects in liver, skeletal muscles and adipocytes through in cardiac myocytes and fibroblasts promoting cardiac hypertrophy and fibrosis. Both diabetes mellitus and hyperglycaemia induce this which can be prevented by inhibition of RAS. Adipokines are cytokines secreted by adipocytes, adipokines have significance in type-2 diabetes and insulin resistance and interact with most organs in the body.

Different kinds of adipokines:
Leptin: Leptin is involved in food intake. It is found to have detrimental effects on the heart including negative ionotropy and decreased cardiac efficiency. However, leptin protects heart from lipotoxicity associated with diabetic cardiomyopathy.

Adiponectin: This is involved in beta oxidation in muscle and suppresses glucose production in liver which maintain the energy homeostasis in the body. A depressed level of adiponectin therefore leads to myocardial infarction and heart failure.

Resistin: Studies have proven that pro-inflammatory action of resistin promotes insulin resistance in various tissues. It was even found that resistin modulates glucose metabolism, insulin signalling and contractile mechanism in diabetic heart.

Therapeutic options
Diagnosis of diabetic cardiomyopathy can be made by echocadiographic techniques and echocardiography screening. Achievements of diabetic control are low with agents that reduce insulin resistance. In the future the availability of agents that prevent glycosylation and cross linking of collagen or decrease lipotoxicity may be developed.

Various possible treatments in diabetic cardiomyopathy:
Beta-blockers: Beta-blockers mainly shift the metabolism of the myocardium from the use of free fatty acids to that of glucose. Use of third generation beta-blocker such as carvedilol which through its alpha-1 blockade has the advantage of vasodilatation and lowering of insulin resistance. Therefore, it provides a distinct advantage in diabetic patients.

Thiazolidinediones: They also shift the metabolism of myocardium from the use of free fatty acid. They have been found to decrease the myocardial fatty acid content and their toxic metabolites and improve ventricular function. Eg. Ranolazine.

ACE inhibitors: The initiative for the treatment of diabetic cardiomyopathy is the use of ACE inhibitors. These drugs decrease left ventricular hypertrophy and myocardial fibrosis, prevent myocardial remodelling, improve endothelial function and lower insulin resistance. Eg. captopril, enalapril, lisinopril, rampril. Either spironolactone or eplerenone because of anti-fibrotic effect in the myocardium also seen to be a logical therapy. Cell based therapy and genetic correction of abnormalities in cardiac excitation-contraction coupling and insulin signalling are emerging as potential strategies in the treatment of heart failure.