Abstract / Summary
Prediabetes is a key precursor stage of type 2 diabetes mellitus (T2DM). Appropriate dietary interventions at this stage can delay or even prevent T2DM development. Stevioside (SV), a natural sweetener, has been reported to have anti-diabetic potential, yet its effect and mechanism on skeletal muscle remains unclear. This study aimed to investigate the effect of SV on glucose uptake in skeletal muscle in prediabetic mice and the underlying molecular mechanism. Prediabetic mouse model was constructed using high-fat diet and subsequent treatment of SV for 8 weeks. Metabolic conditions were assessed via glucose tolerance tests and biochemical assays. RNA-sequencing of gastrocnemius muscle tissue was performed to identify potential signaling pathways. We further validated the findings using pathway-specific inhibitors and targeted gene knockdown in palmitate-induced C2C12 myotubes. SV significantly ameliorated fasting hyperglycemia, glucose intolerance, muscle glycogen content and dyslipidemia in prediabetic mice. RNA-sequencing and molecular analyses revealed that SV mediated the JAK2/STAT3 signaling pathway and upregulated IL6ra expression in gastrocnemius muscle. In vitro experiments demonstrated that SV reversed palmitate-induced glucose uptake impairment, restoring p-JAK2 and p-STAT3 levels and IL6ra expression. JAK2/STAT3 inhibitors decreased the metabolic benefits of SV on glucose uptake. Results from the IL6ra knockdown further supported IL6ra as a downstream effector molecule in the JAK2/STAT3 pathway. In summary, we identified the JAK2/STAT3/IL6ra axis as a new mechanism by which SV enhanced skeletal muscle glucose uptake in prediabetes. Our findings suggest that SV may serve as an effective dietary strategy to prevent the progression of T2DM.