**6. Diabetes induced cardiomyopathy (DCM)**

CVDs are closely associated with diabetes-induced hyperglycaemia, resulting in the death in 80% of people with diabetes [1]. Diabetic cardiomyopathy (DCM) is defined as a disorder of the heart muscle caused by diabetes. It results in pathological cardiac remodelling without previous incidence of CAD, hypertension and valvular disease. The exact cellular, subcellular and molecular mechanisms of DCM are complex and remain unclear [2]. Thus, further studies are essential for better understanding of the mechanism(s) of DCM and also in reversing the pathological cardiac remodelling induced by diabetes [3]. The increased frequency of HF in diabetic patients can persist despite correction for age, obesity, hypercholesterolemia and CAD. DCM is characterized by diastolic dysfunction, which can lead to the development of systolic dysfunction [36]. Echocardiography for patients with type 1 diabetes mellitus (T1DM) without known CAD shows diastolic dysfunction with a reduction in early diastolic filling, increase in atrial filling, an extension of iso-volumetric relation and increased numbers of supra-ventricular premature beats. The most common abnormality observed in asymptomatic diabetics is left ventricular (LV) diastolic dysfunction, likely resulting from greater LV myocardial and vascular stiffness [37]. A deep understanding of its development is necessary for the early diagnosis and subsequent treatment of diabetes-related cardiovascular diseases.

There is a rapidly growing literature on DCM investigating the structural, functional and metabolic changes that occur in the diabetic myocardium and how these changes contribute to the development of DCM in humans [38, 39]. The structural changes include left ventricular hypertrophy, interstitial fibrosis, increased cell death and oxidative stress and myocardial lipotoxicity [40, 41]. The functional changes include diastolic dysfunction, systolic dysfunction and impaired contractile reserve. Metabolic changes include altered substrate utilisation and mitochondrial dysfunction [42]. In type 2 diabetes mellitus (T2DM), left ventricular mass is an independent marker of cardiovascular risks that often occur independently of atrial blood pressure. Hence, diabetes is an independent risk factor leading to left ventricular hypertrophy, myocardial stiffness and inflammation [43]. DCM is also characterized by interstitial fibrosis, mostly composed of collagen and perivascular fibrosis [44]. In biopsies from diabetic heart patients, the deposition of collagen around the vessel and between myofibres is significantly raised. Furthermore, lipofuscin (which is a brown pigment composed of lipid-containing residues), cholesterol and myocardial triglyceride is also significantly increased in cardiac tissue biopsies from the left ventricle [45].

During DCM, hyperglycaemia (HG) can lead to both acute reversible cellular metabolism damage and irreversible changes in endogenous macromolecules in the heart [46]. Elevated blood HG can affect many organs in the body including the kidneys, the eyes, the nerves and the heart resulting in long-term damage and failure [47, 48]. The first target of HG-induced damage is the microvasculature. As a result, the small blood vessels will initiate a systematic complication [49, 50]. Increased oxidative stress (OS) is a key contributor to HG-induced diabetic damages [51]. Increased OS is a possible biochemical mechanism linking the onset of DM and its complications due to OS [52–54]. Furthermore, hypertrophy and myocardial fibrosis are also associated with endothelial cell dysfunction (ECD), inflammation and abnormal vascular remodelling seen in DCM [45]. The activation of endothelial cells (ECs) from a quiescent phenotype to vasoconstriction, pro-inflammatory and pro-apoptotic state can also result in ECD [55]. The exposure of the blood vessels to high fluctuating levels of elevated blood glucose (HG) is a known factor for ECD [56].

An increase in myocardial stiffness is an early sign in the pathogenesis of DCM. This increase in myocardial tissue stiffness is a result of increased collagen production by fibroblasts along with the fibrotic replacement of apoptotic/necrotic cells [57]. Collagen type I and type III fibres accumulate in the epicardial (EPI) layer of the heart and perivascular domains, whereas type IV is mostly found in the endocardial (ENDO) layer of the myocardium [58]. The increased stiffness in diabetic hearts may be due to an increase in the stiffness of cardiac myocytes within the myocardium. Although the changes in stiffness are not dramatic, they may be enough to cause or to contribute to increased cardiac workload over time, leading to DCM progression [59]. At the molecular level, DCM leads to prolongation and enhanced temporal dispersion of the repolarization phase of cardiac action potential (CAP) in myocytes leading to alterations of the spatial heterogeneity of ion channel expression and AP duration [60]. The major recognised factors of DCM are insulin resistance (IR) and hyperinsulinemia [61]. A disruption of insulin-mediated glucose metabolism occurs during IR and hyperinsulinemia which can significantly alter the efficiency of metabolism in cardiac muscle as well as skeletal muscle. The diabetic heart is affected by insulin in both systematic metabolism abnormalities via direct effects on insulin signalling pathways in the myocardium [62]. The early recognised change in insulin resistance in the heart is the impaired ability of insulin to increase glucose transport [63]. Recently, it was found that IR is linked to cardiac contractile dysfunction. In addition, a previous study, has developed a new IR rat model in which the animals were fed on a high cholesterol fructose (HCF) diet [63]. These results demonstrate that IR is directly linked to biochemical changes in the heart, thereby contributing to the development of DCM. Despite the recent advances in this field, our understanding of the initiation and progress of DCM is still very limited.
