Diabetes is a major medical issue worldwide. Several complications are linked to diabetes, including nephropathy, retinopathy, neuropathy, and cardiomyopathy. In our study, induction diabetes was conducted by intraperitoneal injection of STZ. The STZ-induced diabetes is not mechanistically understood. However, since STZ is a chemical analogue of glucose, it is permeated in beta cells, inducing a subsequent cytotoxic reaction that generates reactive nitrogen and oxygen species which by turn damage the beta cells that secret the insulin. Diabetes induction leads to loss of weight due to reduced lipogenesis and enhanced utilization of fats as an energy source (Beylot 1996, Garg et al. 2017).
Diabetic cardiomyopathy is usually connected with electrocardiographic, and histopathological abnormalities (Jia et al. 2016). The anatomical signs of diabetic cardiomyopathy are left ventricular dilatation that accompanied with to left ventricular dysfunction in the early diastolic filling with enhanced isovolumetric relaxation duration (Jia et al. 2016). Systolic dysfunction would be followed by symptomatic heart failure (Lee et al. 1997). The cardiac dysfunction is believed to be raised from the stiffness of cardiomyocytes, cardiac fibrosis, and cardiac hypertrophy (Lee et al. 1997). This dysfunction stimulates the sympathetic tone, which leads to an increased activity of sarcoplasmic reticulum by exaggerated stimulation of β-receptors and ryanodine receptors leading to an intensification of Ca++ release and ventricular tachycardia (Assis et al. 2019). In Addition, cardiomyopathy can be developed due to inflammatory reactions or cardiac fibrosis (Krejci et al. 2016). The extreme liberation of Ca++ ions from the sarcoplasmic reticulum in cardiomyocytes could cause irregular repolarization, which could explain the prolongation in QT and QTc intervals (Paavola et al. 2016). Development of diabetic cardiomyopathy will lead to the formation of left ventricular bundle block, which might result in dyssynchronous activation of the left ventricles. This dysfunction in ventricular conductivity might justify the prolongation of the QRS complex (Akgun et al. 2014). Cardiac dysfunction in the current model progressed to ischemic dilated cardiomyopathy. This could be explained by the observed atrial arrhythmias observed in our study and (Ducas &Ariyarajah 2013). Furthermore, ischemic dilated cardiomyopathy was ensured by an increase in ST-segment elevation. Diabetic cardiomyopathy is a cardiomyopathy that takes place in the absence of notable coronary artery disease (Jia et al. 2018). however, diabetic cardiomyopathy could be accompanied with coronary vascular abnormalities that may affect the coronary blood flow. Decreasing coronary supply and myocardial perfusion will result in impairing the ventricular function which leads to subsequent clinical outcomes (Sandesara et al. 2018). Several structural and functional abnormalities in coronary blood vessels may occur in diabetics; luminal obstruction, infiltration of inflammatory cells and vascular fibrosis as structural changes while functional changes include dysfunction endothelial cells dysfunction, impaired vasorelaxation and vasoconstriction, diminished cardiac perfusion (Sandesara et al. 2018).
The advancement of dilated diabetic cardiomyopathy would stimulate fibrosis, which is considered a familiar marker for cardiomyopathy (Ho et al. 2010). The reduction in adenosine triphosphate (ATP) levels could lead to impaired perfusion and energetics of cardiomyocytes. This would result in reduced cardiac functionality, in addition to microvascular abnormalities (Raman et al. 2019). The modified cardiac functions encourage mutations in the genes encoding myofibers proteins, which may lead to an enhanced fibrosis (Araco et al. 2017).
Many proteins are incorporated in cardiac myofibers contractions. Troponin is one of these proteins. Three complex proteins represent troponin; troponin C, I, and T (Kraus et al. 2018). The detection of cTnT along with CK-MB in plasma is crucial for the diagnosis of cardiac dysfunctions (C.C. et al. 2010). CK enzyme is important for the conversion of creatinine with the assistance of ATP molecules to form phosphocreatine and adenosine diphosphate (ADP) (Bessman &Carpenter 1985). CK is differentiated into three isoforms that are distributed in different body tissues. CK-MB is mainly found in cardiac muscles, CK-MM is expressed in skeletal muscles and CK-BB, the brain CK isoform (Schlattner et al. 2006). The damage of CK-rich tissue will lead to high CK levels detected in plasma (Schlattner et al. 2006). Therefore, detection of cTnT and CK-MB in plasma could be used for the diagnosis of cardiomyopathy, as was previously described by other clinical (Ali et al. 2016, Odum &Young 2018) and animal studies (Al-Rasheed et al. 2017).
NF-κB is believed to regulate inflammatory reactions by enhancing the production of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β (Gianello et al. 2019, Saber et al. 2019a, Zhai et al. 2020). This inflammatory response is quick, as NF-κB is previously stored inactivated form in the cytoplasm. Moreover, activated NF-κB stimulates cardiac hypertrophy and fibrosis (Nakamura &Sadoshima 2018). Diabetes is always coupled with elevated ROS activity and stimulation of the renin-angiotensin-aldosterone system, which results in the subsequent increase in NF-κB formation and excess of pro-inflammatory cytokines (Jia et al. 2016, Saber et al. 2019b, Thomas et al. 2014). These mediators are responsible for the quick progression of diabetic cardiomyopathy (Ali et al. 2020, Yu et al. 2003). The elevated levels of TNF-α and IL-6 could impair the capability of cardiomyocytes to handle the Ca++ ions through lowering the sarcoplasmic/endoplasmic reticulum Ca++ ATPase production (Villegas et al. 2000). This was previously shown in type I model of diabetes induced by STZ in mice, where IL-6 knock out lessened the progress of diabetic cardiomyopathy and enhanced cardiac function (Zhang et al. 2016). Moreover, NF-κB activation increased the release of ROS (Saber et al. 2021), which could be due to the increased activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Mariappan et al. 2010). Pyrrolidine dithiocarbamate derived inhibition of NF-κB restored cardiac function in diabetic animals and improved the mitochondrial structural integrity and prevented oxidative stress (Mariappan et al. 2010).