Dapagliflozin Improves Skeletal Muscle Insulin Sensitivity through SIRT1 activation Induced by Nutrient Deprivation State

Lipid peroxidation and mitochondrial damage impair insulin sensitivity in skeletal muscle. Sirtuin-1 (SIRT1) protects mitochondria and activates under energy restriction. This study investigates whether dapagliflozin (Dapa) can trigger nutrient deprivation to activate SIRT1 and enhance insulin sensitivity in skeletal muscle. We treated diet-induced obese (DIO) mice with Dapa and measured metabolic parameters, lipid accumulation, oxidative stress, mitochondrial function, and glucose utilization in skeletal muscle. Ketogenesis is the most important feature of the nutrient deprivation state, so β-hydroxybutyric acid (β-HB) administration was used in C2C12 myotubes to verify the effect. The role of SIRT1 was verified by RNA interference. We found that the Dapa-induced nutrient deprivation state was characterized by increased lipolysis, urinary glucose excretion, ketogenesis. What’s more, Dapa treatment reduced lipid deposition and oxidative stress, improved mitochondrial function and glucose tolerance in skeletal muscle. The same positive effects were observed after β-HB intervening for C2C12 myotubes, and the promoting effects on glucose utilization were diminished by SIRT1 RNA interference. Thus, Dapa promotes a nutrient deprivation state and enhances skeletal muscle insulin sensitivity via SIRT1 activation. In this study, we identified a novel hypoglycemic mechanism of Dapa and the potential mechanistic targets.