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 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.

Keywords: HDACi; HDACs; diabetes mellitus; glucose metabolism; histone deacetylase; histone deacetylase inhibitor; insulin release; sirtuin activaton; sirtuins.

Figure 1

Figure showing different biological activities of HDAC inhibitors (HDACis) that promote the expression of NGN3 and islet progenitor cell numbers, their differentiation into the β/δ cell lineage, embryonic stem cell differentiation into islet-like clusters/specification, and trans-differentiation of bone marrow-/adipose-derived stem cells into insulin-producing cells.

Figure 2

Schematic diagram showing the role of HDACs in regulating β cell function and insulin secretion. (A) Acetylation of histone H4 is increased in the insulin promoter when glucose levels are high due to the interaction of Pdx1 with CBP, HAT p300 (acetylated H4, relaxed chromatin and increased insulin expression); (B) Pdx1 recruits HDAC 1 and HDAC 2 to the insulin promoter when glucose levels are low, to inhibit H4 acetylation resulting in a decline in insulin production (deacetylated H4, tight chromatin and decreased insulin expression); (C) NeuD1 role in promoting insulin gene expression by the acetylation of p300-associated factor (PCAF) and MafA phosphorylation when glucose levels are high.

Figure 3

Schematic diagram showing the role of HDACs in glucose homeostasis (A) and in developing insulin resistance (B). A. Insulin binding at insulin receptor (IR) stimulates IRS-1 substrate phosphorylation and PI3K binding at it that converts PIP2 into PIP3 by phosphorylation under normal physiological condition. PIP3 phosphorylates Akt/PkB and activates its signaling, promoting translocation of GLUT4 to the plasma membrane and activating its function in glucose uptake and glycogenesis. Akt also causes FOXO1-mediated suppression of PEPCK and G6Pase, the two key gluconeogenic genes. Simultaneously, Akt possesses an alternative control on glycogenesis by deactivating GSK-3β and thereby inhibiting glucose to glycogen conversion. HDACs (especially HDAC2 and 5) here control GLUT4 expression and thereby regulate glucose metabolism in adipocytes and muscle cells. The schematic model below shows the role of HDACs, especially controls of HDAC1 on Pdx1 and SIRT1 on UCP2 functions respectively in insulin signaling under differential glycemic conditions. B. HDACs role in developing insulin resistance. HDACs and HDAC1 bind to IRS-1 and limit its phosphorylation and further endorse FOXO1 deacetylation resulting in HNF4α-led induction of PEPCK via JNK2/STAT3 axis, instigating gluconeogenesis in the liver. On the other hand, HDACs, especially HDAC4 and 5, suppress GLUT4 by deacetylation and impede glucose utilization that contributes to developing insulin resistance.

Figure 4

Schematic diagram showing the role of HDAC3 and 5 in PPARγ deacetylation and insulin resistance. Low-grade inflammation in T2DM and Glucose uptake by GLUT4 that produces ROS collectively activates NF-κB function. It modulates HDAC3/5 to deacetylate PPARγ and inactivate its function that contributes to insulin resistance; however, it can be overcome by HDAC3/5 inhibition. GLUT4 Enhancer Factor (GEF) interaction with MEF2A and HDAC3/5 regulates GLUT4 promoter activity acquiring insulin resistance; however, inhibition of HDAC3/5 can increase GLUT 4 expression and prevent insulin resistance.

Figure 5

Schematic diagram showing the role of HDACs in diabetic nephropathy. HDAC2 inhibition by HDACi induces expression of DNA binding/differentiation 2 (Id2) and bone-morphogenic protein 7 (BMP7) that represses downstream TGF-β1 signalling and subsequently declines fibronectin, collagen 1, α- SMA, and E- cadherin expressions; and thereby, it provides protection either from diabetic nephropathy or nephromegaly.