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 four 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 novel interventional strategies for metabolic disorders/complications.
Highlights
Diabetes mellitus (DM), a group of chronic metabolic disorders, is characterized by a persistently elevated blood glucose level due to deficiency and/or responsiveness of insulin [1]
histone deacetylase (HDAC) inhibitors (HDACis) were intrinsically identified to inhibit cell proliferation in multiple cancer cell lines. These HDACis activities are known to be associated with modulated regulatory tumor suppressor gene activities caused by altered histone acetylation status that is a key event in chromatin remodeling [35]
This review provides insights into the emerging roles of all four classes of HDACs in the developmental and pathogenetic pathways associated with DM
Summary
Diabetes mellitus (DM), a group of chronic metabolic disorders, is characterized by a persistently elevated blood glucose level due to deficiency and/or responsiveness of insulin [1]. Among two main types of diabetes mellitus, type 1 DM (T1DM) is caused by the absolute insulin deficiency due to damage of insulin-producing pancreatic β cells, whereas type 2 DM (T2DM) is associated with insulin resistance, which may give rise to a relative deficiency of insulin [2] In both cases, interactions between the genes and the environment are responsible for developing the syndrome [3,4]. T2DM accounts for >90% of all diabetic disease and promotes microvascular (retinopathy, nephropathy and neuropathy) and macrovascular complications (cardiovascular comorbidities), due to persisted hyperglycaemia and developing insulin resistance (metabolic) syndrome [7] It causes huge psychological and physical strains to patients and put an enormous burden on them for healthcare management [8,9].
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