Insights into the Role of DNA Methylation and Protein Misfolding in Diabetes Mellitus

Abstract

Background: Diabetes mellitus is a metabolic disorder that is characterized by impaired glucose tolerance resulting from defects in insulin secretion, insulin action, or both. Epigenetic modifications, which are defined as inherited changes in gene expression that occur without changes in gene sequence, are involved in the etiology of diabetes. Methods: In this review, we focused on the role of DNA methylation and protein misfolding and their contribution to the development of both type 1 and type 2 diabetes mellitus. Results: Changes in DNA methylation in particular are highly associated with the development of diabetes. Protein function is dependent on their proper folding in the endoplasmic reticulum. Defective protein folding and consequently their functions have also been reported to play a role. Early treatment of diabetes has proven to be of great benefit, as even transient hyperglycemia may lead to pathological effects and complications later on. This has been explained by the theory of the development of a metabolic memory in diabetes. The basis for this metabolic memory was attributed to oxidative stress, chronic inflammation, non-enzymatic glycation of proteins and importantly, epigenetic changes. This highlights the importance of linking new therapeutics targeting epigenetic mechanisms with traditional antidiabetic drugs. Conclusion: Although new data is evolving on the relation between DNA methylation, protein misfolding, and the etiology of diabetes, more studies are required for developing new relevant diagnostics and therapeutics.

Downregulation of SOX11 in fetal heart tissue, under hyperglycemic environment, mediates cardiomyocytes apoptosis

“…[ 17,18 ] DNA methylation is the most widely studied epigenetic mechanism, leading to deregulated gene expression in cancer, diabetes, and psychiatric disorders. [ 19‐21 ] However, the role and molecular bases of DNA methylation in regulating heart development in a hyperglycemic environment remain unclear. Thus, the identification and characterization of a novel gene and DNA methylation regulatory mechanism associated with GDM‐induced congenital malformations are needed.…”

Diabetes Mellitusta Metabolik Hafızanın Rolü

“…Bu mekanizmalar ışığında metabolik hafızanın uzun süreli, zararlı etkilerini açıklanabilir. 4,19 DCCT ve EDIC çalışmasında yer alan tip 1 DM'li hastaların kan monosit ve lenfosit hücrelerindeki DNA ve kromatin analizinde, DCCT çalışması boyunca standart tedavi alan hastaların monosit hücrelerindeki inflamatuvar gen ekspresyonunun (H3K9ac geni), yoğun tedavi alan hastalara kıyasla anlamlı olarak daha yüksek olduğu saptanmıştır. 2, 3, 20 DCCT'yi takiben gerçekleştirilen EDIC çalışmasında, DCCT sürecinde standart tedavi alan hastaların yoğun tedavi alan hastalara kıyasla nefropati ve retinopati yaşama sıklıklarının anlamlı olarak daha sık olduğu gözlenmiştir.…”

Association between metal mixture exposure and abnormal glucose metabolism in multiple mixture exposure models: Evidence from NHANES 2015–2016

“…In addition, there is a study indicating that metals can interfere with protein folding and aggregation ( Tamás et al, 2014 ). Considering the pathogenesis of T2DM, the misfolding and aggregation of islet amyloid polypeptid damage the islet cells and contribute to the development of diabetes ( Ahmed et al, 2019 ). Previous studies evaluated the association between single metal exposure and type 2 diabetes, but these results remain conflicting.…”