Stevioside Improves Liver Insulin Resistance in Prediabetic Mice via IRS1/PI3K/AKT Signaling Pathway

Prediabetes progression to type 2 diabetes mellitus (T2DM) can be effectively prevented by adequate dietary intervention via improved liver insulin resistance. Stevioside, as a natural and safe sweetener, has been shown to have antidiabetic properties. However, whether stevioside can enhance liver insulin resistance in prediabetes remains unclear. We therefore aimed to investigate the effect and molecular mechanisms of stevioside on liver insulin resistance in prediabetes. Prediabetic mice were induced using a high-fat diet and treated with stevioside for 8 weeks. The effects of stevioside on gene expression levels and signaling pathways in the mice liver were investigated by RNA-seq and gene enrichment analysis. We also treated the palmitic acid-induced insulin-resistance AML-12 cells with stevioside,  and measured glucose uptake in insulin-stimulated cells with 2-NBDG. The expression levels of genes and proteins related to the insulin signaling pathway were detected using qRT-PCR and Western blotting. Stevioside improved glucose tolerance and plasma insulin levels in prediabetic mice with insulin resistance and enhanced liver function. Stevioside could improve liver insulin resistance via IRS1/PI3K/AKT signaling pathway in prediabetic mice. Similarly, stevioside decreased the level of p-IRS1 and increased the levels of p-PI3K p85α, AKT, and p-AKT in AML-12 cells. Stevioside could improve glucose tolerance in prediabetic mice with insulin resistance, and ameliorate liver insulin resistance by regulating the IRS1/PI3K/AKT signaling pathway. These results may support stevioside as a potential dietary approach for preventing prediabetes progression to T2DM.