Aim: To examine the role of plasma glucose (GLU), insulin (INS) and glucagon (GG) changes in EGP stimulation during glucosuria (UGE) following SGLT2i administration.

Methods: Using tracer (3-3H-glucose), 30 T2D patients (Age=55±1y, BMI=32.2±0.7kg/m2, FPG=140±6mg/dl, A1c=7.3±0.1%) received three 300-min procedures at 2-weeks intervals: (I) control clamp (CON) with no glucose/hormone infusions; (II) pancreatic clamp (PAN) with somatostatin (0.75mg/h), basal replacement of insulin (0.1mU/kg.min) and glucagon (0.3ng/kg.min); (III) isoglycemic clamp (ISO) with variable dextrose infusion to maintain GLU equal to baseline. Prior to start of each clamp subjects received placebo (PCB, n=10) or dapagliflozin 10mg (DAPA, n=20).

Results: After DAPA (CON), INS decreased (-7±1µU/ml) while GG increased (+10±1pg/ml) (both p<0.05 vs. PCB). Despite UGE of 0.48mg/kg.min, GLU decline was modest (-31±1) due to a “paradoxical” rise in EGP after DAPA. During PAN with DAPA and PCB, INS and GG were unchanged from baseline, and EGP stimulation in DAPA compared to PCB still increased, yet GLU decline was modest (-28.4±3.0). During ISO, EGP decreased markedly with DAPA as well as PCB despite similar plasma GG and INS concentrations.

Conclusion: DAPA-induced glucosuria stimulation of EGP cannot be entirely explained by the rise in plasma glucagon or decline in plasma insulin.

graphic
View largeDownload slide
Disclosure

M. Alatrach: None. C. Agyin: None. N. Laichuthai: None. J.M. Adams: None. M. Abdul-Ghani: None. C.L. Triplitt: Consultant; Self; Abbott. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc. R.A. DeFronzo: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Elcelyx Therapeutics, Inc., Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk Inc. E. Cersosimo: None.

© 2019 by the American Diabetes Association.
2019
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 http://www.diabetesjournals.org/content/license.