The Emerging role of HDACs: Pathology and Therapeutic targets in Diabetes Mellitus

Abstract

Diabetes mellitus (DM) is one of the principal manifestations of metabolic syndrome and its prevalence with modern lifestyle is increasing incessantly. Chronic hyperglycemia can induce several vascular complications that were referred to be the major cause of morbidity and mortality in DM. Although several therapeutic targets have been identified and accessed clinically, the imminent risk of DM and its prevalence are still ascending. Substantial pieces of evidence revealed that histone deacetylase (HDAC) isoforms can regulate various molecular activities in DM via epigenetic and post-translational regulation of several transcription factors. To date, 18 HDAC isoforms have been identified in mammals that were categorized into 4 different classes. Classes I, II, and IV are regarded as classical HDACs, which operate through a Zn-based mechanism. In contrast, class III HDACs or Sirtuins depend on nicotinamide adenine dinucleotide (NAD+) for their molecular activity. Functionally, most of the HDAC isoforms can regulate β cell fate, insulin release, insulin expression and signaling, and glucose metabolism. Moreover, the roles of HDAC members have been implicated in the regulation of oxidative stress, inflammation, apoptosis, fibrosis, and other pathological events, which substantially contribute to diabetes-related vascular dysfunctions. Therefore, HDACs could serve as the potential therapeutic target in DM towards developing novel intervention strategies. This review sheds light on the emerging role of HDACs/isoforms in diabetic pathophysiology and emphasized the scope of their targeting in DM for constituting the novel interventional strategies for metabolic disorders/complications.

Knowledge domain and emerging trends in diabetic cardiomyopathy: A scientometric review based on CiteSpace analysis

“…DCM has been a concern by scholars since it was proposed in 1972, but the related research on DCM did not show explosive growth until 2004 (3,7). Researchers have studied the pathogenesis of DCM from different perspectives, such as impaired myocardial insulin signaling, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, impaired calcium homeostasis, abnormal coronary microcirculation, activation of the sympathetic nervous system (SNS), activation of the renin-angiotensin-aldosterone system (RAAS), and maladaptive immune responses (8)(9)(10)(11)(12)(13)(14)(15). There is a lack of accurate diagnostic criteria for DCM.…”

Molecular and cellular mechanisms in diabetic heart failure: Potential therapeutic targets

“…Although autophagy is important for maintaining cellular homeostasis in healthy cardiac tissues by preventing the accumulation of dysfunctional organelles and cytotoxic protein aggregates, some recent research has found that this process is frequently impaired in diabetic hearts (91). There are contradictory evidences regarding whether autophagy flux is upregulated or downregulated in the hearts of DM patients.…”

Perspectives for Forkhead box transcription factors in diabetic cardiomyopathy: Their therapeutic potential and possible effects of salvianolic acids

“…Appropriate programmed cell death such as apoptosis and autophagy seems to be an essential part in the elimination of cytotoxic proteins and dysfunctional organelles which would otherwise accelerate the development of DCM and the deterioration of DCM to cardiac failure. And, more and more evidences revealed that suppression of excessive cardiomyocyte death of aforementioned death modes occurred in the diabetic heart may yield tremendous advantageous effects on DCM (126)(127)(128). It is well known that FoxO1 and/or FoxO3a participate in the regulation of various cell death seen during insulin resistance and diabetes.…”

“…With apoptosis, FoxO transcription factors are downstream targets of the Akt kinase which regulates processes of cellular proliferation and survival and also may indirectly stimulate expression of death receptor ligands such as Fas ligand through the unstable mitochondrial channels or directly induce the expression of multiple pro-apoptotic proteins like Bcl-2 family (18,25,129). As for autophagy, researchers have shown that plenty of the regulation and control mechanisms include but are not limited to the mTOR/AMPK, FoxOs, SIRTs, and others signalings, and further studies to unmask the detailed roles and in particular the potentially complicated interplays of the pathways should help to elucidate the inconsistent outcomes observed following the intervention of the individual pathways in the treatment of DCM (127,130). Convincing evidences showed that certain drugs protected pancreatic β-cells by enhancing autophagy such as liraglutide (a long-acting human glucagonlike peptide-1 analog), which protected insulinoma cells via alleviating apoptosis accompanied by a significant increase of autophagy under hyperglycemia in vitro (131).…”