{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T23:57:20Z","timestamp":1793750240120,"version":"4.6.1"},"reference-count":57,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"720","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:p>Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the<jats:italic>SLC2A2<\/jats:italic>gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS,<jats:italic>SLC2A2<\/jats:italic>expression was ablated in mouse kidney and HK-2 proximal tubule cells.<jats:italic>GLUT2<jats:sup>Pax8Cre+<\/jats:sup><\/jats:italic>mice developed time-dependent glycogen accumulation in proximal tubule cells and recapitulated the renal Fanconi phenotype seen in patients. In vitro suppression of GLUT2 impaired lysosomal autophagy as shown by transcriptomic and biochemical analysis. However, this effect was reversed by exposure to a low glucose concentration, suggesting that GLUT2 facilitates the homeostasis of key cellular pathways in proximal tubule cells by preventing glucose toxicity. To investigate whether targeting proximal tubule glucose influx can limit glycogen accumulation and correct symptoms in vivo, we treated mice with the selective SGLT2 inhibitor dapagliflozin. Dapagliflozin reduced glycogen accumulation and improved metabolic acidosis and phosphaturia in the animals by normalizing the expression of Napi2a and NHE3 transporters. In addition, in a patient with FBS, dapagliflozin was safe, improved serum potassium and phosphate concentrations, and reduced glycogen content in urinary shed cells. Overall, this study provides proof of concept for dapagliflozin as a potentially suitable therapy for FBS.<\/jats:p>","DOI":"10.1126\/scitranslmed.abn4214","type":"journal-article","created":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T17:58:19Z","timestamp":1698861499000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":20,"title":["The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0622-6612","authenticated-orcid":true,"given":"Francesco","family":"Trepiccione","sequence":"first","affiliation":[{"name":"Department of Medical Translational Sciences, University of Campania \u201cLuigi Vanvitelli,\u201d 80131 Naples, Italy."},{"name":"Biogem, Institute of Molecular Biology and Genetics, 83031 Ariano Irpino, 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