Interindividual variance in diabetes susceptibility: Role of the liver transcriptome and methylome

Background/Aims:

The development of type 2 diabetes (T2D) is driven by genetic as well as environmental factors. However, even genetically identical mice show a broad variation in T2D onset upon high-fat feeding. The aim of this study was to investigate if differential DNA methylation can be linked to the observed variations in gene expression and thereby predicting the onset of T2D.

Methods:

Discrimination between diabetes-resistant (DR) and diabetes-prone (DP) female New Zealand Obese mice is based on liver fat content combined with early blood glucose levels at 10 weeks of age. This prediction enabled us to isolate metabolically relevant tissues such as liver several weeks before disease onset. Liver transcriptome and methylome was analyzed using RNA sequencing and whole genome bisulfite sequencing, respectively.

Results:

Liver transcriptome analysis revealed 1372 transcripts to be differentially expressed between DR and DP mice, mainly regulating fatty acid metabolism and citrate cycle. Additionally, we identified 455,782 CpG sites differentially methylated between both groups. Next, the overlap of both datasets as well as stringent filtering criteria (significant correlation of CpG methylation and gene expression and conservation of the CpG between mouse and human) led to the identification of 151 CpG sites corresponding to 112 transcripts, enriched in insulin signaling, to be the most relevant hepatic alterations preceding T2D.

Conclusion/Outlook:

In the liver, several genes involved in insulin action are affected by DNA methylation. Additionally, the most promising candidates will be analyzed in blood cells in order to evaluate them as T2D biomarker in humans.