The Impact of Epigenetics on the Pathophysiology of Type 2 Diabetes and Associated Nephropathic Complications

Abstract

Type 2 diabetes (T2D) is a long-term metabolic condition that presents considerable health challenges globally. As the disease progresses, the interplay between genetic, environmental, and lifestyle factors becomes increasingly evident, leading to complications. Epigenetics has emerged as a critical area of research, providing insights into how these factors can modify the expression and cellular behavior without altering the underlying DNA sequence. Various epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulation, drive cell dysfunction, inflammation, and fibrosis, aggravating diabetes and its complications. Amongst all the complications diabetic kidney disease (DKD) also known as diabetic nephropathy (DN), is a significant microvascular complication often regarded as a silent killer, as early diagnosis remains highly complicated. This review investigates various epigenetic modifications associated with T2D and DKD, employing a database search strategy incorporating the PICO framework method to ensure comprehensive coverage of relevant literature. Advancements in epigenome profiling provide valuable insights into the functional outcomes and chromatin states of cells impacted by T2D. Understanding epigenetics thus emphasizes its crucial role in the development and progression of T2D and transition to DKD, while also highlighting the potential reversibility of epigenetic modifications and potency as a biomarker for predicting DKD. More extensive research is needed to identify specific epigenetic mechanisms involved in DKD to further refine predictive models and therapeutic strategies. This unified exploration of significant epigenetic modifications offers a focused analysis of how these alterations influence the trajectory of disease and presents new avenues for therapeutic intervention.

Keywords: DNA methylation; Epigenetics; diabetic kidney disease (DKD); diabetic nephropathy (DN); histone modification; micro-RNA; type 2 diabetes (T2D).

Figure 1

Schematic diagram of epigenetic changes.[12]

Figure 2

Basic epigenetic mechanisms for the regulation of gene expression

Figure 3

Epigenetic risk factors associated with type 2 diabetes[2437]

Figure 4

Epigenetics of impaired insulin production in T2D

Figure 5

A Schematic representation illustrates altered DNA methylation of genes at different sites in T2D subjects. Some of these genes also exhibit modified gene expression and have been proven to impact traits related to diabetes, such as insulin secretion

Figure 6

Persistent hyperglycemia in T2D diabetic nephropathy activates various pathways and causes cellular stress. This disrupts epigenetic mechanisms like histone modifications, DNA methylation, and gene regulation by ncRNAs, leading to altered gene expression across tissues and contributing to DN pathogenesis