# Heart Failure and Diabetes Mellitus: Biomarkers in Risk Stratification and Prognostication
## 2 Basic Underlying Mechanisms of HF Development in Diabetics  
Cardiac dysfunction in T2 DM is a result of the development of metabolic abnormalities, attributed to increase fasting glucose, insulin resistance, lipotoxicity, and impaired reparation, sometimes termed diabetic cardiomyopathy, although not widely used [14]. Other causes for the occurrence of HF in diabetics include conventional CV risk factors that include hypertension, dyslipidemia, abdominal obesity, asymptomatic atherosclerosis, CVD, chronic kidney disease (CKD), as well as non-traditional risk factors, such as ectopic calcification and osteoporosis [15; 16; 17]. Consequently, cardiac dysfunction in T2 DM patients is characterized by primary metabolic disturbances, secondary ischemic injury, cardiac myocyte apoptosis, immunological alterations with subsequent subcellular component abnormalities (mitochondrial stress, endoplasmic reticular formation dysfunction, secretome shaping impairment), oxidative stress with reduced nitric oxide bioavailability, fibrosis, local myocardial and microvascular inflammation, impaired cellular signaling (altered calcium homeostasis, activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS)), endothelial dysfunction, and altered tissue reparation [16; 17]. In fact, impaired glucose metabolism, lipotoxicity, altered metabolic memory, and insulin resistance are considered as key factors contributing to mitochondrial stress and myocardial cell injury [17; 18]. Indeed, suppressed AMP kinase activity due to mitochondrial dysfunction and consequently lowered phosphorylation of troponin relates to diastolic dysfunction prior to systolic dysfunction beyond the turnover of myosin chain isoforms [19]. In addition, impaired diabetic cardiac function is a result of insulin-dependent activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B-ACT signaling, which alters titin phosphorylation and consequently leads to titin N2B/N2 BA isoform modification and titin-based myocardial stiffness [20; 21]. There is a large body of evidence regarding the fact that insulin can directly stimulate the expression of a number of hypertrophic genes in cardiac myocyte including \(\beta\)-myosin heavy chain, insulin-like growth factor 1 receptor, myocyte enhancement factor, and brain-type natriuretic peptide (BNP) [22; 23; 24]. Moreover, insulin-like growth factor 1, acting directly as an activator of the insulin receptor and indirectly through extracellular signal-regulated kinase 2 (Erk1/2) and PI3K signaling pathways, mediates cardiac hypertrophy, extracellular remodeling, and suppresses cardiac myocyte apoptosis [25; 26]. The development of cardiac dysfunction in T2 DM is closely associated with hyperactivity of both the RAAS and sympatico-adrenal nervous system (SNS) [27]. Acting as triggers of gluconeogenesis, lipolysis, and glycolysis, catecholamines, angiotensin-II and aldosterone promote the production of advanced glycation end products (AGE), which directly and along with insulin and glucose activate transforming growth factor beta 1 (TGF-\(\beta\)1)/SMAD signaling pathways through appropriate cell surface receptors (RAGE) [28]. Consequently, increased oxidative stress, inflammatory response, and fibrotic extracellular matrix transformation with collagen cross-linking correspond to adverse cardiac remodeling, acceleration of atherosclerosis, and worsening vascular integrity and endothelial function [29; 30; 31]. Of note, impaired GLUT4 and PI3K/Akt/eNOS signaling due to the activation of RAAS and insulin resistance accompany the reduced tyrosine phosphorylation of insulin receptor substrate (IRS)-1/2, which in turn leads to a lowered nitric oxide production. It directly impairs the vasomotor ability of coronary arteries, and substantially decreases in the recruitment, proliferation, and survival of endothelial progenitor cells that play a pivotal role in endogenous vascular reparation [32].