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Review
. 2024 Sep 21:17:3557-3576.
doi: 10.2147/DMSO.S479077. eCollection 2024.

Targeting the Epigenetic Marks in Type 2 Diabetes Mellitus: Will Epigenetic Therapy Be a Valuable Adjunct to Pharmacotherapy?

Chioma Laura Odimegwu  1 , Samuel Nkachukwu Uwaezuoke  1 , Ugo N Chikani  1 , Ngozi Rita Mbanefo  1 , Ken Daberechi Adiele  1 , Charles Emeka Nwolisa  2 , Chizoma Ihuarula Eneh  3 , Chibuzo Obiora Ndiokwelu  1 , Somkenechi C Okpala  1 , Francis N Ogbuka  3 , Kenneth E Odo  1 , Ijeoma Onyinyechukwu Ohuche  1 , Chinelo Elizabeth Obiora-Izuka  1
Affiliations
Review

Targeting the Epigenetic Marks in Type 2 Diabetes Mellitus: Will Epigenetic Therapy Be a Valuable Adjunct to Pharmacotherapy?

Chioma Laura Odimegwu et al. Diabetes Metab Syndr Obes. .

Abstract

Although genetic, environmental, and lifestyle factors largely contribute to type 2 diabetes mellitus (T2DM) risk, the role of epigenetics in its pathogenesis is now well established. The epigenetic mechanisms in T2DM mainly consist of DNA methylation, histone modifications and regulation by noncoding RNAs (ncRNAs). For instance, DNA methylation at CpG islands in the promoter regions of specific genes encoding insulin signaling and glucose metabolism suppresses these genes. Modulating the enzyme mediators of these epigenetic marks aims to restore standard gene expression patterns and improve glycemic control. In targeting these epigenetic marks, using epigenetic drugs such as DNA methyltransferase (DNAMT), histone deacetylase (HDAC) and histone acetyltransferase (HAT) inhibitors has led to variable success in humans and experimental murine models. Specifically, the United States' Food and Drug Administration (US FDA) has approved DNAMT inhibitors like 5-azacytidine and 5-aza-2'-deoxycytidine for use in diabetic retinopathy: a T2DM microvascular complication. These DNAMT inhibitors block the genes for methylation of mitochondrial superoxide dismutase 2 (SOD2) and matrix metallopeptidase 9 (MMP-9): the epigenetic marks in diabetic retinopathy. Traditional pharmacotherapy with metformin also have epigenetic effects in T2DM and positively alter disease outcomes when combined with epigenetic drugs like DNAMT and HDAC inhibitors, raising the prospect of using epigenetic therapy as a valuable adjunct to pharmacotherapy. However, introducing small interfering RNAs (siRNAs) in cells to silence specific target genes remains in the exploratory phase. Future research should focus on regulating gene expression in T2DM using long noncoding RNA (lncRNA) molecules, another type of ncRNA. This review discusses the epigenetics of T2DM and that of its macro- and microvascular complications, and the potential benefits of combining epigenetic therapy with pharmacotherapy for optimal results.

Keywords: DNA methylation; epigenetic therapy; epigenetics; histone modifications; noncoding RNA regulation; therapeutics; type 2 diabetes mellitus.

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Conflict of interest statement

The authors disclose that there are no conflicts of interests.

Figures

Figure 1
Figure 1
Schematic diagram indicating the primary epigenetic mechanisms in type 2 diabetes mellitus (T2DM).
Figure 2
Figure 2
Schematic diagram showing the target sites of some epigenetic drugs in type 2 diabetes mellitus.
See this image and copyright information in PMC

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