802-P: Dapagliflozin Improves Glycolytic Reserve in Peripheral Blood Mononuclear Cells in Patients with Type 1 Diabetes

Abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibition is emerging as a beneficial adjunctive therapy in type 1 diabetes (T1D). It is hypothesized that SGLT2 inhibition relieves hypoxia in the kidneys. As mitochondrial dysfunction might contribute to kidney hypoxia, SGLT2 inhibition could ameliorate hypoxia via restored mitochondrial respiration. Changes in metabolic processes in peripheral blood mononuclear cells (PBMCs) are associated with various diseases including diabetes. PBMCs are an easily accessible reporter cell population to test changes in cellular metabolism caused by changes in blood glucose. The aim of this study was to investigate the effects of a single dose of 50 mg dapagliflozin compared to placebo on PBMCs’ bioenergetics in individuals with T1D in a double blinded randomized crossover study with a two-week washout period. With Seahorse extracellular flux technology, we analysed the efficiency of mitochondrial oxidative phosphorylation and glycolysis in PBMCs obtained from a fresh blood sample of each study participant before and after intervention. Fifteen individuals (33% females) with mean (±SD) age 58 (±14) years and Hba1c 8.0 (±0.6) % were included. Dapagliflozin did not influence PBMC mitochondrial oxidative phosphorylation. However, dapagliflozin significantly improved PBMC glycolytic reserve by 35% (mean ±SE, 3.5 ±0.3 e-6 ECAR/cell number) compared to baseline (2.6 ±0.5 e-6 ECAR/cell number). Our results suggest that dapagliflozin enhances PBMCs’ flexibility to use glycolysis as an energy supply pathway in individuals with T1D. This study advances our mechanistic understanding of the subtle changes in systemic metabolism and the beneficial effects at the cellular level of SGLT2 inhibition in patients with T1D. Disclosure J. Melo: None. J. Laursen: None. N. S. Heinrich: Stock/Shareholder; Self; Akebia Therapeutics, Inc., Novo Nordisk A/S. I. B. Rasmussen: None. C. S. Hansen: None. M. Frimodt-moeller: None. P. Rossing: Advisory Panel; Self; Astellas Pharma Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., Merck KGaA, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi, Vifor Pharma Management Ltd. J. Størling: None.