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

Abstract

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 β 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.

l-Methionine supplementation attenuates high-fat fructose diet-induced non-alcoholic steatohepatitis by modulating lipid metabolism, fibrosis, and inflammation in rats

“…17 Recently, we have shown in our previous study that L-methionine treatment improves diabetes-associated metabolic alterations by modulating the one-carbon cycle metabolites and has the potential to protect against β-cell damage in type 1 diabetes mellitus. 18,19 Despite this extensive but conflicting information with respect to methionine-supplemented diet in hepatic health, not much has been studied regarding the effects of methionine supplementation in diet-induced non-alcoholic steatohepatitis. Hence, in the present study, we aim to assess the effects of L-methionine supplementation on the progression of dietinduced NASH in rats.…”

The metabolic-epigenetic nexus in type 2 diabetes mellitus

“…We have also reported widespread changes to DNA methylation in response to folic acid supplementation, though T2DM-related genes were not specifically examined (Irwin et al, 2019). Navik et al (2019) provides the first evidence that dietary L-methionine supplementation prevents H3K36me2 methylation in a diabetes rodent model. Interestingly, L-methionine was also found to inhibit DNMT1 expression.…”

Hyperglycemic memory in the rat bladder detrusor is associated with a persistent hypomethylated state

“…Our evidence for hyperglycemic memory in the bladder also provides a rationale for the treatment of diabetic patients who have achieved glycemic control, but have recalcitrant DBD, through approaches that target the methylation index in detrusor tissue. For example, there is evidence that dietary supplementation with Methionine prevents diabetes‐induced epigenetic alterations, and therefore it has been proposed that regulating dietary Methionine levels could be therapeutically exploited for the treatment of metabolic diseases (Navik et al., 2019). Another approach might be to use drugs that are known to affect the methylation index of tissues.…”