Interaction between an SGLT2 inhibitor and exercise training.

Abstract

PURPOSE\nExercise 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.\n\n\nMETHODS\nA rodent model of type 2 diabetes (30\u202fmg/kg streptozotocin and high-fat feeding in male Sprague-Dawley rats) was used to assess 12\u202fweeks 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\u202f=\u202f7-10/group): vehicle (0.5% methyl cellulose) sedentary (VEH SED), VEH EX, canagliflozin (3\u202fmg\u202fkg-1d-1) SED (SGLT2i SED), or SGLT2i EX.\n\n\nRESULTS\nBoth 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\u202f±\u202f51 vs 1427\u202f±\u202f82\u202fmmol/L 120\u202fmin-1 for SGLT2i EX vs. SGLT2i SED, respectively; p\u202f<\u202f0.05) and insulin responses (insulin area under the curve 24,524\u202f±\u202f4126 vs. 41,208\u202f±\u202f2714\u202fpmol\u202fL-1 120\u202fmin-1 for SGLT2i EX vs. VEH EX, respectively; p\u202f<\u202f0.05) during an oral glucose tolerance test. Only the combination of SGLT2i EX lowered body weight compared to VEH SED (p\u202f<\u202f0.01). 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\u202f±\u202f183 vs.433\u202f±\u202f33\u202fm for SGLT2i EX and VEH EX, respectively; p\u202f<\u202f0.01), and this was accompanied by a greater reliance on fat as an energy source during exercise (p\u202f<\u202f0.01).\n\n\nCONCLUSIONS\nIf these findings with the combination of SGLT2i and exercise translate to humans, they will have important clinical health implications.