155-LB: The Increase in Endogenous Glucose Production with SGLT2 Inhibition Is Unchanged by Renal Denervation but Highly Correlates to Urinary Glucose Excretion

Abstract

Background: SGLT2 inhibition causes a “paradoxical” increase in EGP, indicating the presence of a “reno-hepatic axis.” Aim: We measured EGP after SGLT2 inhibition in renal transplant subjects with and without type 2 diabetes to evaluate the role of renal nerves and SNS in mediating this “reno-hepatic axis.” Six T2D (A1c = 7.2±0.1) and 8 non-T2D (A1c = 5.6±0.1) with normal renal function and no history of rejection (prednisone ≤ 5mg/day) received two 6-hr measurements of EGP preceded by dapagliflozin or placebo. Results: Following DAPA in T2D, FPG (143±15 to 112±9 mg/dl, p=0.01) and FPI (14±3 to 11±2, p=0.02) decreased while glucagon increased (45±13 to 54±14 pg/mL, p=0.09) (all p<0.05 vs. placebo); plasma epinephrine and norepi did not change from baseline. Following placebo, EGP decreased (p<0.01) in both T2D and non-DM. In contrast, after DAPA EGP increased (p<0.01) in both T2D (by 0.4±0.1 mg/kg.min) and in non-T2D (by 0.1±0.1 mg/kg.min) compared to placebo. The DAPA-induced increment in EGP production was highly correlated (r = 0.824, p<0.001) with the increment in urinary glucose excretion in all subjects (Figure). Conclusions: (1) Renal denervation in renal transplant patients failed to block the DAPA-mediated stimulation of EGP; (2) DAPA-stimulated rise in EGP is strongly related to the increase in urinary glucose excretion blunting the decline in FPG. Disclosure C. Solis-Herrera: Advisory Panel; Self; Sanofi. M. Alatrach: None. C. Agyin: None. H. Honka: None. R. Patel: None. C.L. Triplitt: Consultant; Self; Abbott. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc. J.M. Adams: None. A. Gastaldelli: Consultant; Self; A. Menarini Diagnostics, Eli Lilly and Company, Genentech, Inc., Gilead Sciences, Inc., Inventiva Pharma. M. Abdul-Ghani: None. E. Cersosimo: None. 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.