Combination of Canagliflozin and Exercise Training Leads to Lipid-Dependent Energy Expenditure in Skeletal Muscle in Obese Diabetic Mice

Abstract

Background and Aim: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert multiple metabolic effects. Exercise training is a robust treatment of obesity and diabetes, but the effect of SGLT2 inhibitors on exercise training is unclear. We investigated the association between canagliflozin (CAN) and training effects on skeletal muscle and liver in obese diabetic mice. Method: Male mice loaded with a high-fat diet for 4 weeks were housed in a normal cage (sedentary; sed) or wheel cage (WCR). A total of 0.03%w/w CAN was administrated for 2 weeks. Glucose and lipid metabolism of skeletal muscle (gastrocnemius) was analyzed and compared among 4 groups (control/sed, control/WCR, CAN/sed, and CAN/WCR). Results: Body weight in control/WCR and CAN/sed mice was significantly lower compared with that in control/sed mice, and further weight loss was observed in CAN/WCR mice. There was no difference in running distance between control/WCR and CAN/WCR mice. Control/WCR mice showed lower blood glucose levels than did control/sed mice (200.0±4.2 vs. 231.9±8.7 mg/dL, p=0.01). CAN decreased glucose levels, but there was no difference between CAN/sed (118.9±6.29 mg/dL) and CAN/WCR mice (113.6±4.48 mg/dL). GLUT1 and GLUT4 mRNA levels in skeletal muscle in CAN/sed and CAN/WCR mice were significantly lower than those in control/sed mice. Levels of mRNA of CD36 (× 1.26 in CAN/sed and × 1.31 in CAN/WCR mice, both p<0.05) and CPT1b (× 1.09 in CAN/sed and × 1.21 in CAN/WCR mice, both p<0.05) were significantly higher than those in control/sed mice. CPT1b mRNA levels in CAN/WCR mice were significantly higher than those in CAN/sed mice (p<0.05). Discussion: CAN promoted transition from glucose to lipid-dependent energy metabolism in skeletal muscle and this effect might have been enhanced by concomitant exercise. Conclusion: The combination of CAN and exercise may be effective for weight loss in obesity by an increase in lipid energy expenditure. Disclosure K. Tanaka: Research Support; Self; Mitsubishi Tanabe Pharma Corporation. H. Takahashi: Research Support; Self; Mitsubishi Tanabe Pharma Corporation. K. Sasaki: Employee; Self; Mitsubishi Tanabe Pharma Corporation. K. Inoue: None. Y. Matsuda: None. Y. Eguchi: None. K. Anzai: Research Support; Self; Mitsubishi Tanabe Pharma Corporation, Sysmex Corporation.