Methionine Restriction Increases Insulin Sensitivity in Type-2 Diabetes via miRNA Activation

Abstract

Methionine Restriction (MR) causes a higher level of circulating and hepatic fibroblastic growth factor 21 (FGF21). This leads to metabolic phenotypes, including increased energy expenditure, insulin sensitivity, and extended lifespan. Previous studies on obese mice have concluded that dietary MR in a high-fat regimen prevents hyperglycemia and improves glucose homeostasis, thus preventing type-2 diabetes, a multifactorial metabolic disease characterized by high blood glucose levels and cell insulin resistance. Recent experiments have shown that cells’ response to dietary MR includes changes in methylation of DNA promoters that activate or repress microRNAs (miRNAs), which are small endogenous nucleotide sequences and contain 18-22 base pairs that control gene expression for lipid metabolism. Considering that the disruption of miRNA levels affects insulin resistance, miRNA potentially plays a role in MR to increase insulin sensitivity for type-2 diabetes. In this paper, we investigate the mechanism of MR influencing the expression level of miRNA-15b to promote insulin sensitivity in obese organisms. Using our in-vitro model, we measured the expression of miRNA-15b in adipocytes cultured in MR and control conditions. Additionally, we compared insulin sensitivity and free fatty acid (FFA) metabolite levels between obese mice on control and MR diets. Taken together, we were able to verify the positive effects of MR in reducing hepatic fatty acid production, decreasing blood glucose levels, and increasing insulin sensitivity. However, miRNA-15b downregulates cells’ insulin signaling pathway and insulin sensitivity. Therefore, we proposed potential influences of MR on other miRNAs in reducing lipid cell differentiation and enhancing insulin sensitivity for future investigation.