Epigenetic Changes in Islets of Langerhans Preceding the Onset of Diabetes

Abstract

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 semiexplorative approach identified 497 differentially expressed and methylated genes ( P = 6.42e-09, hypergeometric test) enriched in pathways linked to insulin secretion and extracellular matrix-receptor interaction. The comparison of mouse data with DNA methylation levels of incident T2D cases from the prospective European Prospective Investigation of Cancer (EPIC)-Potsdam cohort, revealed 105 genes with altered DNA methylation at 605 cytosine-phosphate-guanine (CpG) sites, which were associated with future T2D. AKAP13 , TENM2 , CTDSPL , PTPRN2 , and PTPRS showed the strongest predictive potential (area under the receiver operating characteristic curve 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 humans with T2D. Using 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.

Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease

“…Other variants in the TENM2 gene were associated with multiple traits including smoking status (p=1.6×10 -17 ) and BMI (p=2.6×10 -8 ) in the UK Biobank. Furthermore, it was previously reported that the DNA methylation status in TENM2 is among the strongest predictors of incident type 2 diabetes 46 .…”

MiR‐205 is up‐regulated in islets of diabetes‐susceptible mice and targets the diabetes gene Tcf7l2

“…For each group (B6‐ ob/ob and NZO), five samples (each containing islets of one to two mice) were sequenced by GATC (Konstanz, Germany) on an Illumina HiSeq platform. Quality control and bioinformatic analysis were described previously 43 . Only transcripts with an absolute fold change >0.7 were considered for further analysis.…”

“…Quality control and bioinformatic analysis were described previously. 43 Only transcripts with an absolute fold change >0.7 were considered for further analysis. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis was performed using the David data base tool 7, 44 with cut-off fold enrichment set to >1.7 and enriched P value <.05.…”

DNA Methylation Patterning and the Regulation of Beta Cell Homeostasis

“…In fact, such epigenetic changes can occur preceding T2D, as illustrated by a recent study in diabetic mice, that identified DNA methylation changes associated with differential expression of several genes. Notably, the differentially methylated and expressed genes were enriched in pathways associated with insulin secretion (161). Similarly, islets from obese mice show an upregulation of Dnmt3a, which leads to increased Nkx6.1 promoter methylation, reduced Nkx6.1 and insulin expression, and consequently, impaired islet function (162).…”