Patients with type 2 diabetes (T2DM) are at increased risk for developing cardiovascular disease (CVD). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are antidiabetic agents that significantly reduce the risk of acute myocardial infarction, stroke and CV death in patients with T2DM. However, the physiologic, metabolic and molecular mechanism of this cardioprotective effect are unclear. Given our preliminary and published findings, we hypothesized that SGLT2i may regulate mitochondrial function in the heart to improve cardiac function in the context of obesity and T2DM. We treated high-fat diet (HFD)-fed mice with canagliflozin (CANA; 10 mg/kg/day) for 1-week, and examined mitochondrial function in the heart, as well as in skeletal muscle, kidney and liver. Glucose tolerance tests were performed before and after treatment, and blood was collected at the end of the study to quantitate plasma lipids and ketones. Isolated mitochondria were provided with either pyruvate/malate (P/M) or palmitoylcarnitine/malate (PC/M) in the absence or presence of ADP to analyze basal and state III respiration. The CANA treatment prevented HFD-induced glucose intolerance independent of changes in body weight or free fatty acids (FFA), but significantly increased plasma ketones. The HFD markedly increased ATP-linked oxidation of PC/M in cardiac mitochondria, which was completely prevented by short-term CANA treatment. Canagliflozin did not affect pyruvate oxidation in the heart and had no effect on mitochondrial function in the other tissues tested. These data suggest that SGT2i may improve cardiovascular health through primary effects on mitochondrial metabolism. Further studies are needed to relate these metabolic effects of SGLT2i to improved cardiac function in vivo.
I. Flores: None. C. Shannon: None. M. Fourcaudot: None. T. Bakewell: None. L. Norton: None.