Combined Exercise Training and Sodium‐glucose Cotransporter 2 Inhibition Improves Glycemic Control and Exercise Tolerance When Compared to Pharmacotherapy Alone in a Model of Type 2 Diabetes
Authors: Linden Melissa A. , Ross Trenton T. , Beebe David A. , Hamilton Karyn L. , Miller Benjamin F. , Braun Barry , Esler William P. 
Published: June 2021

Regular exercise (EX) is recommended in addition to pharmacotherapies for the management of type 2 diabetes (T2D), but patients with T2D often have difficulty tolerating EX. Additionally, some studies report that the combination of metformin, the first line pharmacotherapy for T2D, and EX may have non‐additive or even inhibitory effects on glycemic control and aerobic capacity. Therefore, further investigation into the combination of EX with alternative T2D medications is needed. The objectives of this study were to 1) determine whether co‐treatment with a sodium‐glucose cotransporter 2 inhibitor (SGLT2i), a new class of T2D medication, and EX further improve glycemic control when compared to SGLT2i alone and 2) assess whether the addition of SGLT2i to EX affects exercise tolerance. It was hypothesized that SGLT2i combined with EX would further improve indices of glycemic control when compared to SGLT2i alone and that the combination of therapies would not worsen exercise tolerance. All procedures performed were in accordance with established regulations and guidelines and were approved by the Pfizer IACUC. A low‐dose streptozotocin (30 mg/kg) and high‐fat feeding model was used to induce T2D in male Sprague Dawley rats. Animals were then randomized to the following conditions (n=7–10 animals/group): vehicle (0.5% methylcellulose) and sedentary (VEH SED), VEH EX, canagliflozin (3 mg/kg/d) SED (SGLT2i SED), or SGLT2i EX for 12 weeks. EX consisted of treadmill running for 60 min/d, 5d/wk, on a 10% incline at ~50–55% of the maximal running speed obtained from a VO2peak test. Reported values are the mean ± SEM. EX had lower body weight (p<0.05) and body fat percentage (p<0.01) compared to SED. SGLT2i EX tended to have ~10% lower body weight than VEH EX (p=0.07), with similar body fat percentage (p=0.74 vs. SGLT2i SED). EX improved glucose (glu) area under the curve ~27% (AUC; p<0.001 vs SED) during a glucose tolerance test, with no differences between VEH EX and SGLT2i EX (p=0.08). SGLT2i had lower fasting glu and insulin, HOMA‐IR, glu AUC, and insulin AUC vs. VEH (p<0.05 for each). SGLT2i EX demonstrated further improvements in HOMA‐IR (3.0±1.0 vs. 6.5±1.2, p≤0.05) and glu AUC (19976± 934 vs. 25718± 1483 mg/dl/120 min, p=0.01), and tended to have lower insulin AUC (140±24 vs 160±23 ng/ml/120 min, p=0.056) vs. SGLT2i SED. As expected, EX had higher VO2peak and maximal running speed during VO2peak (p<0.05), with no differences between EX groups. Interestingly, at submaximal running speeds (50–75% maximal running speed), SGLT2i EX ran further before fatigue than VEH EX (882±183 vs 417±34 m, p<0.05); this was accompanied by a lower respiratory exchange ratio (0.81 vs 0.86, p<0.01) at the same VO2. When taken together, these findings suggest that the combination of SGLT2i and EX may further improve glycemic control vs. SGLT2i alone. Additionally, the combination of therapies may improve exercise tolerance, which could have potent metabolic effects in this population.Support or Funding InformationAuthors TTR, DAB, and WPE are employees and shareholders of Pfizer. MAL is a former employee of Pfizer. BB has consulted for Pfizer, Inc. MAL, KLH, BFM, and BB have received research funding from Pfizer, Inc.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.