L-Methionine prevents β-cell damage by modulating the expression of Arx, MafA and regulation of FOXO1 in type 1 diabetic rats

L-Methionine (L-Met) is an essential sulphur-containing amino acid having a vital role in various key cellular processes. Here we investigated the effect of L-Met on streptozotocin-induced beta-cell damage model of diabetes mellitus in Sprague Dawley rats. At the end of study biochemical parameters, immunoblotting, qRT-PCR and ChIP-qPCR are performed. L-Met was administered orally (250 and 500 mg/kg/day) to diabetic animals for 8 weeks improved plasma glucose and insulin levels. Pancreas immunohistochemistry showed significant increase in insulin expression, decrease in glucagon and Bax expression. Interestingly, L-Met inhibited the expression of Arx; upregulated MafA and FOXO1 which play a critical role in the maintenance of beta-cell identity. Our data also showed a decrease in H3K27me3 and an increase in H3K4me3 ( bivalent domain alteration) in diabetic rats and these recovered by L-Met. Furthermore, the chromatin-immunoprecipitation assay showed a decreased enrich-ment of H3K27me3 on the promoter of the FOXO1 gene in diabetic rats and L-Met prevents this decrease. Our results showed the first evidence of the involvement of H3K27me3 in regulating the expression of the FOXO1 gene and the prevention of beta-cell injury by L-Met treatment. In conclusion, we report the involvement of L-Met in the modulation of alpha-cell identity marker (Arx), beta-cell identity marker (MafA) and regulation of FOXO1 by histone methylation marks for the first time. We are of the opinion that this employed as a novel therapeutic approach for mitigating diabetes-induced beta-cell death.

Automated summary

In this study, we investigated the effect of L-Methionine (L-Met) on streptozotocin-induced beta-cell damage model of diabetes mellitus in rats. Our results showed that L-Met improved plasma glucose and insulin levels, increased insulin expression, and inhibited the expression of Arx. Furthermore, L-Met regulated the expression of FOXO1 through histone methylation marks H3K27me3 and H3K4me3. These findings suggest that L-Met may be a potential therapeutic approach for preventing beta-cell injury in diabetes.