The antidiabetic SGLT2 inhibitor canagliflozin reduces mitochondrial metabolism in a model of skeletal muscle insulin resistance

Abstract

AbstractAimsSodium‐glucose cotransporter 2 (SGLT2) inhibitors such as canagliflozin (CANA) have emerged as an effective adjuvant therapy in the management of diabetes, however, past observations suggest CANA may alter skeletal muscle mass and function. The purpose of this work was to investigate the effects of CANA on skeletal muscle metabolism both with and without insulin resistance.MethodsC2C12 myotubes were treated with CANA with or without insulin resistance. Western blot and qRT‐PCR were used to assess protein and gene expression, respectively. Cell metabolism was assessed via oxygen consumption and extracellular acidification rate. Mitochondrial, nuclei and lipid content were measured using fluorescent staining and microscopy.ResultsCANA decreased mitochondrial function and glycolytic metabolism as did insulin resistance, however, these changes occurred without significant alterations in gene expression associated with each pathway. Additionally, while insulin resistance reduced insulin‐stimulated pAkt expression, CANA had no significant effect on insulin sensitivity.ConclusionsCANA appears to reduce mitochondrial and glycolytic metabolism without altering gene expression governing these pathways, suggesting a reduction in substrate may be responsible for lower metabolism.