Dapagliflozin Impairs the Suppression of Endogenous Glucose Production in Type 2 Diabetes Following Oral Glucose

OBJECTIVE To examine the effect of SGLT2 inhibitors (SGLT2i) on endogenous glucose production (EGP) in patients with type 2 diabetes after an oral glucose load. RESEARCH DESIGN AND METHODS Forty-eight patients with type 2 diabetes received an 8-h [3-H-3]-glucose infusion (protocol I) to assess EGP response to: 1) dapagliflozin (DAPA), 10 mg; 2) exenatide (EXE), 5 lg s.c.; 3) DAPA/EXE; and 4) placebo (PCB). After 2 weeks (protocol II), patients were restudied with a 5-h double-tracer (i.v. [3-3H]-glucose and oral [1-C-14]-glucose) oral glucose tolerance test (OGTT) preceded by PCB, DAPA, EXE, or DAPA/EXE. RESULTS Protocol I: EGP decreased (P<0.01) with PCB (2.16 +/- 0.15 to 1.57 +/- 0.08 mg/kg/min) and EXE (2.13 +/- 0.16 to 1.58 +/- 0.03) and remained unchanged (P = NS) with DAPA (2.04 +/- 0.17 vs. 1.94 +/- 0.18) and DAPA/EXE (2.13 +/- 0.10 vs. 2.09 +/- 0.03). During OGTT, EGP decreased (P<0.01) with PCB (2.30 +/- 0.05 to. 1.45 +/- 0.06 mg/kg/min) and EXE (2.53 +/- 0.08 to 1.36 +/- 0.06); with DAPA (2.20 +/- 0.04 vs. 1.71 +/- 0.07) and DAPA/EXE (2.48 +/- 0.05 vs. 1.64 +/- 0.07), the decrease in EGP was attenuated (both P < 0.05). During OGTT, the insulin/glucagon (INS/GCN) ratio increased in PCB (0.26 +/- 0.03 vs. 0.71 +/- 0.06 lU/mL per pg/mL), whereas in DAPA (0.26 +/- 0.02 to 0.50 +/- 0.04), the increase was blunted (P < 0.05). In EXE, INS/GCN increased significantly (0.32 +/- 0.03 to 1.31 +/- 0.08) and was attenuated in DAPA/EXE (0.32 +/- 0.03 vs. 0.78 +/- 0.08) (P<0.01). CONCLUSIONS These findings provide novel evidence that the increase in EGP induced by SGLT2i is present during an oral glucose load. The fact that stimulation of EGP occurs despite elevated plasma insulin and glucagon suggests that additional factors must be involved.