Effect of Dapagliflozin on Renal and Hepatic Glucose Kinetics in T2D and NGT Subjects

Acute and chronic sodium–glucose cotransporter 2 (SGLT-2) inhibition increases endogenous glucose production (EGP). However, the organ—liver versus kidney— responsible for the increase in EGP has not been identi-fied. In this study, 20 subjects with type 2 diabetes (T2D) and 12 subjects with normal glucose tolerance (NGT) received [3-³H]glucose infusion (to measure total EGP) com-bined with arterial and renal vein catheterization and para-aminohippuric acid infusion for determination of renal blood flow. Total EGP, net renal arteriovenous balance, and renal glucose production were measured before and 4 h after dapagliflozin (DAPA) and placebo administration. Following DAPA, EGP increased in both T2D and NGT from baseline to 240 min, while there was a significant time-related decrease after placebo in T2D. Renal glucose production at baseline was <5% of basal EGP in both groups and did not change significantly following DAPA in NGT or T2D. Renal glucose uptake (sum of tissue glucose uptake plus glucosuria) increased in both T2D and NGT following DAPA (P < 0.05 vs. placebo). The increase in renal glucose uptake was entirely explained by the increase in glucosuria. A single dose of DAPA significantly increased EGP, which primarily is explained by an increase in hepatic glucose production, establishing the existence of a novel renal-hepatic axis.