Pharmaco-Epigenetics and Epigenetic Drugs in Type 2 Diabetes: Can Epigenetics Predict Drug Efficiency?

Abstract

Type 2 Diabetes Mellitus (T2DM) is increasingly affecting individuals across various age groups due to inadequate insulin action and secretion. It has become the leading cause of mortality worldwide, with an estimated 9.3% of the global population currently affected. Recent epigenetic studies have shown that variations such as DNA methylation and histone modifications are implicated in the development of T2DM. However, epigenetically related conditions are known to be reversible, which could potentially pave the way for predicting and treating T2DM. This has led to the development of epigenetic modifier drugs, including histone deacetylase inhibitors (HDACi), histone acetyltransferase inhibitors (HATi), protein arginine methyltransferase inhibitors (PRMTi), DNA methyltransferase inhibitors (DNMTi), histone demethylating inhibitors (HDMi), and sirtuin-activating compounds (STAC). A major challenge with these epigenetic drugs is that only a few have been approved for treating metabolic diseases due to their potential to negatively impact off-target genes. The low specificity of these drugs can lead to side effects and increased toxicity, contributing to complex diseases such as cancer. Hence, gaining a comprehensive understanding of the epigenetic mechanisms underlying metabolic diseases can provide new insights and strategies for preventing, diagnosing, and treating metabolic disorders, such as T2DM. This review summarizes the epigenetic variations in T2DM, pharmaco-epigenetics, and the challenges surrounding epigenetics. This provides basic insight into the discovery of novel drug targets, which can lead to the development of epigenetic therapies for T2DM. Hence, the reversible nature of epigenetic variations retains hope for future novel strategies to combat T2DM.

Keywords: DNA methylation; diabetes mellitus; epi-drugs; epigenetics; histone modifications.

Figure 1

The diagrammatic illustration of epigenetic modifications, which include DNA methylation, histone modifications, and miRNAs. (A) Mechanism of miRNA synthesis. The enzyme called RNA polymerase II transcribes miRNA genes into pri-miRNAs, which are then cleaved by Drosha and DGCR8 into a hairpin structure called pre-miRNAs. The pre-miRNAs are then transported into the cytoplasm by Exportin-5, where Dicer cleaves pre-miRNAs into double-stranded RNAs. One strand is incorporated into the RNA-induced silencing complex (RISC) to guide mRNA targeting, while the other is degraded. (B) The core histones undergo histone modifications, which include histone methylation (me), where methyl groups are added to histone proteins, acetylation (Ac), where an acetyl group is added to histone proteins, and phosphorylation (P), where a phosphate group is added to specific amino acids within the tail of histone proteins. (C) DNA methylation, whereby DNMT enzymes add a methyl group to DNA. Source: Adapted from Desiderio et al. [15]. Created with BioRender.com.

Figure 2

The DNA methylation and demethylation mechanism. cytosine (C); S-adenosylmethionine (SAM); S-adenosylhomocysteine (SAH); 5-methylcytosine (5meC); 5-carboxylcytosine (5caC); 5-formylcytosine (5fC); 5-hydroxymethylcytosine (5hmC); DNA methyltransferase (DNMT); ten eleven translocation enzyme (TET); thymine-DNA-glycosylase (TDG); base excision repair (BER). Created with ChemDraw 23.0 professional software.