Empagliflozin Enhances Total-Body Norepinephrine Turnover in Parallel with Stimulation of Hepatic Gluconeogenesis and Ketone Production in Type 2 Diabetes

Introduction and Objective: SGLT2 inhibitors lower plasma glucose yet paradoxically increases hepatic glucose production (HGP)/gluconeogenesis and ketone production. Whether activation of the sympathetic nervous system (SNS), assessed by norepinephrine turnover, mediates these effects in humans remains unclear.To measure the effect of empagliflozin on HGP/gluconeogenesis, plasma ketone and FFA concentrations, and total-body NE turnover in T2DM diabetes. Methods: 15 patients with type 2 diabetes (Age = 57 ± 2 yrs, HbA1c = 9.0 ± 1.0%, BMI = 31 ± 1.5 kg/m²) participated in the study. HGP, gluconeogenesis and total-body NE turnover were measured with 6,6-²H2 -Glucose, D2O and 3H-NE, respectively, before and 5 hours after empagliflozin (25 mg) ingestion. Plasma glucose, insulin, C-peptide, free fatty acid (FFA), and ketone concentrations, NE specific activity, and deuterium enrichment in glucose were measured over 5 hours. Results: After empagliflozin administration, gluconeogenesis increased from 1.57 to 1.77 mg/kg/min (p<0.01) without change in HGP 2.33 to 2.43 mg/kg/min (p=NS). NE turnover increased by 82% from 689 ± 69 to 1238 ± 183 ng/min (p<0.01), in association with a 40% increase in NE clearance rate (1596±224 to 2218±339 ml/min, p<0.05). Plasma norepinephrine concentration increased from 297 to 335 pg/mL p = 0.03). Plasma FFA (0.512 to 0.705 mmol/L, p < 0.001) and plasma ketone (0.358 to 0.538 mmol/L, p = 0.006) concentrations increased markedly. Insulin declined from 17 to 14 µU/mL (p = 0.04) in response to the glucosuria - induced decline plasma glucose concentration. Conclusion: Acute empagliflozin administration causes a rapid (within 5 hours) increase norepinephrine turnover, indicating SNS activation. The increase in sympathetic activity explains the increases in plasma FFA and ketone concentrations and augmented the rate of gluconeogenesis observed following empagliflozin administration. Disclosure: A. Merovci: None. H. Zaitoon: None. A. Gastaldelli: Consultant; Current; Boehringer Ingelheim International GmbH. Speaker's Bureau; Current; Boehringer Ingelheim International GmbH. Other - educational grant; Ended; Boehringer Ingelheim International GmbH. Other - educational grant; Current; Eli Lilly and Company. Consultant; Ended; Merck Sharp & Dohme Corp. Speaker's Bureau; Ended; Merck Sharp & Dohme Corp. Other - grant reviewer; Ended; Pfizer Inc. Advisory Panel; Ended; Novo Nordisk Global Business Services. Speaker's Bureau; Ended; Novo Nordisk Global Business Services. Advisory Panel; Ended; Regeneron Pharmaceuticals Inc. Other - educational grant; Current; Madrigal Pharmaceuticals, Inc. Speaker's Bureau; Ended; Madrigal Pharmaceuticals, Inc. M. Lalovich: None. S. Pezzica: None. J.M. Adams: None. A.O. Chavez-Velazquez: Advisory Panel; Ended; Crinetics Pharmaceuticals, Inc. A.A. Hansis-Diarte: None. M. Abdul-Ghani: None. R.A. DeFronzo: Advisory Panel; Ended; AstraZeneca. Research Support; Current; AstraZeneca. Advisory Panel; Current; Novo Nordisk. Research Support; Current; Eli Lilly and Company. Advisory Panel; Current; Corcept Therapeutics. Speaker's Bureau; Current; Corcept Therapeutics. Consultant; Current; Alnylam Pharmaceuticals, Inc. Advisory Panel; Current; Regeneron Pharmaceuticals Inc., Aardvark. Funding: NIH NIDDK (5 RO1 DK024092-40)