The combination of exercise training and sodium-glucose cotransporter-2 inhibition improves glucose tolerance and exercise capacity in a rodent model of type 2 diabetes

Abstract

Purpose: Exercise is recommended in addition to pharmacotherapies for the management of type 2 diabetes, but metformin and exercise training may have non-additive or even inhibitory effects on exercise-induced improvements in glycemic control and exercise capacity. The objectives of this report were to determine if co-treatment with a sodium-glucose cotransporter-2 inhibitor and exercise could (1) further improve glycemic control when compared to either monotherapy and (2) not worsen exercise capacity when compared to exercise alone.

Methods: A rodent model of type 2 diabetes (30 mg/kg streptozotocin and high-fat feeding in male Sprague-Dawley rats) was used to assess 12 weeks of co-treatment with a sodium-glucose cotransporter 2 inhibitor (SGLT2i) and exercise (EX; treadmill running) on glycemic control and exercise capacity. Animals were randomized to the following conditions (n = 7-10/group): vehicle (0.5% methyl cellulose) sedentary (VEH SED), VEH EX, canagliflozin (3 mg kg^-1 d^-1) SED (SGLT2i SED), or SGLT2i EX.

Results: Both EX and SGLT2i independently improved indices of glycemic control. The combination of SGLT2i and EX further improved glucose tolerance (glucose area under the curve 1109 ± 51 vs 1427 ± 82 mmol/ L 120 min^-1 for SGLT2i EX vs. SGLT2i SED, respectively; p < 0.05) and insulin responses (insulin area under the curve 24,524 ± 4126 vs. 41,208 ± 2714 pmol L^-1 120 min^-1 for SGLT2i EX vs. VEH EX, respectively; p < 0.05) during an oral glucose tolerance test. Only the combination of SGLT2i EX lowered body weight compared to VEH SED (p < 0.01). SGLT2i caused several metabolic adaptations including increased ketone production and a greater reliance on fat as a source of energy during normal cage activity. Interestingly, animals that were given the SGLT2i and underwent exercise training (SGLT2i EX) had better submaximal exercise capacity than EX alone, as indicated by distance run prior to fatigue (882 ± 183 vs.433 ± 33 m for SGLT2i EX and VEH EX, respectively; p < 0.01), and this was accompanied by a greater reliance on fat as an energy source during exercise (p < 0.01).

Conclusions: If these findings with the combination of SGLT2i and exercise translate to humans, they will have important clinical health implications.

Keywords: Energy expenditure; Exercise capacity; Exercise training; Metabolism; SGLT2 inhibitor; Substrate utilization.