Genes Related to Type 2 Diabetes and Insulin Resistance are Hypomethylated after Bariatric Surgery

de Toro-Martín J1,2, Guénard F1,2, Tchernof A2,3, Deshaies Y3,4, Marceau P5, Vohl MC1,2

1. Institute of Nutrition and Functional Foods, Laval University, Quebec, QC, Canada; 2. School of Nutrition, Laval University, Quebec, QC, Canada; 3. Quebec Heart and Lung Institute, Quebec, QC, Canada; 4. Department of Medicine, Laval University, Quebec, QC, Canada; 5. Department of Surgery, Laval University, Quebec, QC, Canada

Background and aims: Biliopancreatic diversion with duodenal switch (BPD-DS) is a widely recognized bariatric surgery in weight loss programs. BPD-DS is also associated with significant post-surgery metabolic improvements, mainly with a decrease in insulin resistance (IR) and resolution of type 2 diabetes (T2D). However, the specific mechanisms by which metabolic improvements occur after BPD-DS are still not fully elucidated. To gain understanding of the factors predisposing to metabolic improvements after weight loss surgery, our aim was to investigate the potential role of epigenetic determinants in this process by identifying the methylation signature of genes associated to T2D and IR after BPD-DS.

Materials and methods: Whole-genome methylation levels at cytosine-phosphate-guanine (CpG) dinucleotides were measured in blood DNA (Infinium HumanMethylation450 BeadChips) of 20 women post- bariatric surgery (BPD-DS group) with a mean follow-up of 12 years and 20 pre-surgical women with severe obesity (control group). Participating women were matched for age, pre-surgery body mass index and metabolic parameters. A pathway-based differential methylation analysis was performed between the two groups for a set of genes involved in T2D and IR (T2D-IR genes), according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways (IDs: 04930 and 04931).

Results: Differential methylation analysis was performed for 3,984 CpG sites, corresponding to 133 T2D-IR unique genes. A total of 811 CpG sites belonging to 119 T2D-IR genes (89.5% of genes) remained significantly different after Bonferroni correction (P<1.43x10-7). The majority of the differentially methylated CpG sites (60.8%) showed differences greater than 10%, and 97.2% of these sites were found to be significantly hypomethylated whereas 2.8% were overmethylated in the BPD-DS group versus the control group. The analysis of CpG sites within promoter regions revealed that five hypomethylated genes directly involved in insulin signaling (INSR, PIK3CG, PTEN, IRS1 and AKT2) exhibited the greatest differences in methylation levels between groups.

Conclusion: These preliminary results show that most genes involved in T2D and IR pathways exhibited significant differences in methylation levels after BPD-DS when compared to a pre-surgery control group. The majority of them were significantly hypomethylated, suggesting an effect of bariatric surgery on the epigenetic signature of genes involved in glucose homeostasis. Further studies are needed to establish a causal relationship between methylation changes in T2D-IR genes and metabolic outcomes after bariatric surgery.