The SGLT2-inhibitor dapagliflozin improves neutropenia and neutrophil dysfunction in a mouse model of the inherited metabolic disorder GSDIb

Roberta Resaz; Federica Raggi; Daniela Segalerba; Chiara Lavarello; Alessandra Gamberucci; Maria Carla Bosco; Simonetta Astigiano; Antonia Assunto; Daniela Melis; Mariavittoria D'Acierno; Maria Veiga-da-Cunha; Andrea Petretto; Paola Marcolongo; Francesco Trepiccione; Alessandra Eva

doi:10.1016/j.ymgmr.2021.100813

The SGLT2-inhibitor dapagliflozin improves neutropenia and neutrophil dysfunction in a mouse model of the inherited metabolic disorder GSDIb

Mol Genet Metab Rep. 2021 Oct 20:29:100813. doi: 10.1016/j.ymgmr.2021.100813. eCollection 2021 Dec.

Authors

Roberta Resaz¹, Federica Raggi¹, Daniela Segalerba¹, Chiara Lavarello², Alessandra Gamberucci³, Maria Carla Bosco¹, Simonetta Astigiano⁴, Antonia Assunto⁵, Daniela Melis⁶, Mariavittoria D'Acierno^{7

8}, Maria Veiga-da-Cunha^{9

10}, Andrea Petretto², Paola Marcolongo³, Francesco Trepiccione^{7

8}, Alessandra Eva¹

Affiliations

¹ Laboratory of Molecular Biology, IRCCS Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy.
² Core Facilities-Clinical Proteomics and Metabolomics, IRCCS, Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, 16147 Genova, Italy.
³ Department of Molecular and Developmental Medicine, Università degli Studi di Siena, Siena, Italy.
⁴ Animal Facility, IRCCS Ospedale Policlinico San Martino, Genova, Italy.
⁵ Medical, Surgical, and Dental Department, Università degli Studi di Salerno, Salerno, Italy.
⁶ Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana," Section of Pediatrics, Università degli Studi di Salerno, Via Salvador Allende, 43 84081, Baronissi, Salerno, Italy.
⁷ Biogem Research Institute "Gaetano Salvatore", Ariano Irpino, Italy.
⁸ Department of Translational Medical Sciences, Università degli Studi della Campania "L. Vanvitelli", Naples, Italy.
⁹ Walloon Excellence in Lifesciences and Biotechnology, B-1200 Brussels, Belgium.
¹⁰ Groupe de Recherches Metaboliques, de Duve Institute, UCLouvain, (Université Catholique de Louvain), B-1200 Brussels, Belgium.

Abstract

Glycogen Storage Disease type 1b (GSDIb) is a genetic disorder with long term severe complications. Accumulation of the glucose analog 1,5-anhydroglucitol-6-phosphate (1,5AG6P) in neutrophils inhibits the phosphorylation of glucose in these cells, causing neutropenia and neutrophil dysfunctions. This condition leads to serious infections and inflammatory bowel disease (IBD) in GSDIb patients. We show here that dapagliflozin, an inhibitor of the renal sodium-glucose co-transporter-2 (SGLT2), improves neutrophil function in an inducible mouse model of GSDIb by reducing 1,5AG6P accumulation in myeloid cells.

Keywords: 1,5-anhydroglucitol-6-phosphate; 1,5AG, 1,5-anhydroglucitol; 1,5AG6P, 1,5-anhydroglucitol-6-phosphate; BM, bone marrow; CFU, colony forming units; Dapagliflozin; G-CSF, granulocyte colony stimulating factor; G6PC3, glucose-6-phosphatase C3; G6PT, glucose-6-phospate translocase; GSDIb, Glycogen Storage Disease type 1b; Glycogen storage disease type 1b; M-CSF, macrophage colony stimulating factor; Mouse model; NET, neutrophil extracellular trap; Neutrophils; PMA, phorbol myristate acetate; PRM, parallel reaction monitoring; Renal sodium-glucose co-transporter-2; SGLT2, sodium-glucose co-transporter-2; TM, tamoxifen; fMLP, N-formyl-L-methionyl-L-leucyl-phenylalanine.