SGLT Inhibitors Enhance Endogenous Glucose Productions (EGP) in a Preclinical Animal Model

Aim: SGLT inhibitors was found to paradoxically enhance EGP in type 2 diabetes patients, while reduce EGP in diabetic mice during hyperinsulinemic-euglycemic clamp. In this study, we assess acute and 7-day effects of SGLT inhibitors on EGP in rats by 13C-glucose tracer dilution method to identify a translational rodent model. Method: SD rats aged 7 weeks were assigned to 3 groups (n=6 each), vehicle, LX4211 (10 mg/kg) and canagliflozin (10 mg/kg). On day 1, rats were fasted for 3 hours and dosed with SGLT inhibitors, LX4211 or canagliflozin before a 13C-glucose IV injection (25 mg/kg) 2 hour post drug administration. Blood were collected at 0, 5, 15, 30, 45, 60, 75, 90, 120, and 150 minutes time points. Plasma 13C-glucose and 12C-glucose levels were detected by LC/MS. EGP was calculated by multiplying fractional glucose turnover rate by pool size. After washout and the same 18 rats were dosed for 7 days, EGP were assessed on day 7. Results: 13C--glucose IV injection after acute LX4211 and canagliflozin dosing did not significantly changed plasma glucose concentration over time, but led to a rapid rise in plasma 13C-glucose enrichment followed by a time-dependent decrease of 13C-glucose enrichment. The fractional glucose turnover rate and EGP were 3.14±0.35 (SD) percent and 6.28±0.70 (SD) mg.kg-1.minutes-1 in vehicle group. Single dose of LX4211 and canagliflozin significantly increased EGP by 27.5% and 57.1%, respectively. After 7-days of treatment, the fractional glucose turnover and EGP were 3.30±0.28 (SD) percent and 6.59±0.56 (SD) mg.kg-1.minutes-1 in vehicle group, which was highly consistent to the previous EGP measurement. Moreover, 7 days treatment of LX4211 and canagliflozin significantly elevated EGP by 24.8% and 33.4%, respectively. Conclusion: This study demonstrated that SGLT inhibitors can increase EGP in animal model as in type 2 diabetes patients. Detecting EGP using 13C-glucose tracer dilution method may facilitate the discovery of novel SGLT inhibitors with differential effects on EGP.