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) 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) 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.


S. Huang: None. D. Cai: None. Z. Yue: None. H. Yan: None. Z. Zhou: None. X. Fu: None. H. Wang: None. Y. Tao: None. J.J. Hwa: None.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at