Epigenetic changes in islets of Langerhans preceding the onset of diabetes

The identification of individuals with a high risk of developing type 2 diabetes (T2D) is fundamental for prevention. Here, we used a translational approach and prediction criteria to identify changes in DNA methylation visible before the development of T2D.

Islets of Langerhans were isolated from genetically identical 10-week-old female New Zealand Obese mice which differ in their degree of hyperglycemia and in liver fat content. The application of a semi-explorative approach identified 497 differentially expressed and methylated genes (p-value=6.42e-09, hypergeometric test) enriched in pathways linked to insulin secretion and ECM-receptor interaction. The comparison of mouse data with DNA methylation levels of incident T2D cases from the prospective EPIC-Potsdam cohort, revealed 105 genes with altered DNA methylation at 605 CpG sites which were associated with future T2D. AKAP13, TENM2, CTDSPL, PTPRN2 and PTPRS showed the strongest predictive potential (ROC-AUC values 0.62-0.73). Among the new candidates identified in blood cells, 655 CpG sites, located in 99 genes, were differentially methylated in islets of human with T2D. Utilizing correction for multiple testing detected 236 genes with an altered DNA methylation in blood cells and 201 genes in diabetic islets. Thus, the introduced translational approach identified novel putative biomarkers for early pancreatic islet aberrations preceding T2D.