Elucidating Genetic and Epigenetic Mechanisms of Type 2 Diabetes Mellitus Pathogenesis

Abstract

Type 2 diabetes mellitus (T2DM) is a rapidly escalating public health crisis in Bangladesh, which now ranks seventh globally, with approximately 13.9 million adults living with the disease. T2DM is a multifactorial disorder arising from complex interactions among genetic susceptibility, epigenetic dysregulation, and environmental exposures. Despite the growing burden, molecular-level evidence from Bangladeshi populations remains scarce. This study aimed to investigate the genetic, environmental, and epigenetic factors associated with T2DM in the Bangladeshi population by examining genetic variations in the TCF7L2 rs12255372 and SLC30A8 rs13266634 genes, exploring the association between adverse childhood experiences (ACEs) and adult T2DM risk, characterizing genome-wide DNA methylation alterations in T2DM, and assessing the potential mediating role of DNA methylation in the relationship between ACE exposure and T2DM susceptibility. A case-control study was conducted among Bangladeshi T2DM patients and healthy controls. Clinical, anthropometric, biochemical, and psychosocial data were collected, and ACE exposure was assessed using the standardized ACE questionnaire. Candidate gene polymorphisms were analyzed by PCR amplification and Sanger sequencing. The Structural consequences of the SLC30A8 rs13266634 substitution were investigated via molecular dynamics simulation. Genome-wide DNA methylation profiling was performed using whole-genome enzymatic methyl sequencing on peripheral blood-derived genomic DNA, followed by bioinformatic analysis using the nf-core/methylseq pipeline and differential methylation analyses with edgeR and DMRcate. Pathway enrichment analysis was conducted using Ingenuity Pathway Analysis. High-dimensional mediation analysis (HDMAX2) was applied to explore the potential mediating role of DNA methylation in the association between ACE and T2DM. The study demonstrated that both genetic and environmental factors contribute significantly to T2DM susceptibility in the Bangladeshi population. The TCF7L2 rs12255372 T allele was significantly associated with increased T2DM risk, with individuals carrying either GT or GT-TT genotypes showing higher odds of disease. Similarly, the SLC30A8 rs13266634 wild-type CC genotype and major C allele were associated with increased T2DM susceptibility, whereas the variant TT genotype x appeared to confer a protective effect. Molecular dynamics simulations further suggested that the ZnT8 p.R325W substitution increased structural rigidity and reduced conformational flexibility, potentially affecting zinc transport and insulin granule physiology. In addition to genetic susceptibility, ACEs were strongly associated with T2DM, as individuals exposed to four or more ACEs had more than two-fold higher risk of developing the disease. Genome-wide DNA methylation profiling identified 608 differentially methylated CpG sites, the majority of which were hypermethylated. Pathway enrichment analyses revealed epigenetic dysregulation in neurotransmitter signaling, fatty acid metabolism, adiponectin signaling, insulin resistance pathways, and mitochondrial regulation. Furthermore, high-dimensional mediation analysis identified multiple methylated loci potentially involved in the association between ACE exposure and T2DM, while pooled mediation analysis indicated that the indirect effect through DNA methylation accounted for approximately 41.1% of the total ACE–T2DM association. These findings provide statistical evidence consistent with a potential epigenetic pathway through which early-life adversity may influence adult metabolic disease risk, rather than establishing a definitive causal relationship. In conclusion, this study provides integrated evidence that genetic susceptibility, adverse childhood experiences, and epigenetic dysregulation collectively contribute to T2DM in the Bangladeshi population. The findings enhance understanding of the molecular mechanisms underlying T2DM and may contribute to future strategies for early risk prediction, prevention, and personalized management of diabetes in Bangladesh.