**3.4. Mitochondria and diabetic cardiomyopathy**

Although coronary artery disease remains as the top cause of mortality and morbidity in western countries, the link between HF and diabetes is growing with the rising incidence of diabetes and prediabetes [121]. Based on epidemiological studies, diabetic individuals are likely to develop HF compared to those who have no diabetic history [122]. This link describes the term diabetic cardiomyopathy, which is due to the myocardium of chronic diabetes patients showing diastolic dysfunction and left ventricular hypertrophy, followed by later onset systolic dysfunction that regresses to decompensated HF [123]. Approximately 60% of type 2 diabetic patients have diabetic cardiomyopathy [124]. The causes of diabetic cardiomyopathy are multifactorial and complex. Cardiac mitochondrial abnormalities were found in both diabetic mouse models and human diabetic hearts. Diabetic cardiomyopathy has been linked to the increased myocardial oxygen consumption and increased oxidative stress. Mouse models of type 2 diabetes (*db/db* and *ob/ob*) showed dysfunctional mitochondrial state 3 respiration and decline in ATP production [125, 126]. In right atrial myofibers of diabetic patients, defects in respiratory complex were observed with the reduction of state 3 respiration on impairment in complex I alone [127]. Another respiration deficiency was detected in myofibers from diabetic patients that showed deficiency in respiration with substrate palmitoyl-L-carnitine [127].

Interestingly, opposite to the reduction of FAO in failing heart, diabetic hearts had more FAO and a reduction in glucose oxidation. The increase in FAO is attributed to the increased expression of PPARα, which increases the genes that are involved with cardiac FA utilization [128]. Additionally, in type 2 diabetes, reduction of cardiac efficiency is also caused by an increase in mitochondrial uncoupling that in turn increases O2 consumption. The series of events begins with the increased availability and delivery of FA that forces the mitochondria to increase FA uptake. This stimulates the increase in ROS production [129]. ROS generation activates the uncoupling proteins (UCs) and promotes proton leak via ANT. The increase in mitochondrial uncoupling propagates the increase of mitochondrial O2 consumption, which promotes the activation of FAO. As mitochondrial uncoupling causes the rise in O2 consumption, the ATP production will not be increased. This reduces the cardiac efficiency of the cell in the generation and usage of energy, which subsequently reduces the provision of ATP for the cell and leads to contractile dysfunction. Thus, this is the link between the type 2 diabetes mechanism merging with contractile dysfunction and development of muscle pathology, with diastolic dysfunction and left ventricular hypertrophy.
