Dietary Supplementation of Methyl Donor l-Methionine Alters Epigenetic Modification in Type 2 Diabetes

Scope The aim of the current study is to evaluate whether l-methionine supplementation (l-Met-S) improves type 2 diabetes-induced alterations in glucose and lipid metabolism by modulating one-carbon metabolism and methylation status. Methods and Results Diabetes is induced in male Sprague-Dawley rats using high-fat diet and low dose streptozotocin. At the end of study, various biochemical parameters, immunoblotting, qRT-PCR and ChIP-qPCR are performed. The first evidence that l-Met-S activates p-AMPK and SIRT1, very similar to metformin, is provided. l-Met-S improves the altered key one-carbon metabolites in diabetic rats by modulating methionine adenosyl transferase 1A and cystathione beta synthase expression. qRT-PCR shows that l-Met-S alleviates diabetes-induced increase in Forkhead transcription factor 1 expression and thereby regulating genes involved in glucose (G6pc, Pdk4, Pklr) and lipid metabolism (Fasn). Interestingly, l-Met-S inhibits the increased expression of DNMT1 and also prevents methylation of histone H3K36me2 under diabetic condition. ChIP assay shows that persistent increase in abundance of histone H3K36me2 on the promoter region of FOXO1 in diabetic rats and it is recovered by l-Met-S. Conclusion The first evidence that dietary supplementation of l-Met prevents diabetes-induced epigenetic alterations and regulating methionine levels can be therapeutically exploited for the treatment of metabolic diseases is provided.