The sweet pee model for Sglt2 mutation

Joseph P. Ly, Tuncer Onay, Karen Sison, Gavasker Sivaskandarajah, Venkata Sabbisetti, Lingli Li, Joseph V. Bonventre, Ann Flenniken, Neal Paragas, Jon M. Barasch, S. Lee Adamson, Lucy Osborne, Janet Rossant, Jurgen Schnermann, Susan E. Quaggin

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Inhibiting renal glucose transport is a potential pharmacologic approach to treat diabetes. The renal tubular sodium-glucose transporter 2 (SGLT2) reabsorbs approximately 90% of the filtered glucose load. An animal model with sglt2 dysfunction could provide information regarding the potential long-term safety and efficacy of SGLT2 inhibitors, which are currently under clinical investigation. Here, we describe Sweet Pee, a mouse model that carries a nonsense mutation in the Slc5a2 gene, which results in the loss of sglt2 protein function. The phenotype of Sweet Pee mutants was remarkably similar to patients with mutations in the Scl5a2 gene. The Sweet Pee mutants had improved glucose tolerance, higher urinary excretion of calcium and magnesium, and growth retardation. Renal physiologic studies demonstrated a prominent distal osmotic diuresis without enhanced natriuresis. Sweet Pee mutants did not exhibit increased KIM-1 or NGAL, markers of acute tubular injury. After induction of diabetes, Sweet Pee mice had better overall glycemic control than wild-type control mice, but had a higher risk for infection and an increased mortality rate (70% in homozygous mutants versus 10% in controls at 20 weeks). In summary, the Sweet Pee model allows study of the long-term benefits and risks associated with inhibition of SGLT2 for the management of diabetes. Our model suggests that inhibiting SGLT2 may improve glucose control but may confer increased risks for infection, malnutrition, volume contraction, and mortality.

Original languageEnglish (US)
Pages (from-to)113-123
Number of pages11
JournalJournal of the American Society of Nephrology
Volume22
Issue number1
DOIs
StatePublished - Jan 2011

ASJC Scopus subject areas

  • Nephrology

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    Ly, J. P., Onay, T., Sison, K., Sivaskandarajah, G., Sabbisetti, V., Li, L., Bonventre, J. V., Flenniken, A., Paragas, N., Barasch, J. M., Adamson, S. L., Osborne, L., Rossant, J., Schnermann, J., & Quaggin, S. E. (2011). The sweet pee model for Sglt2 mutation. Journal of the American Society of Nephrology, 22(1), 113-123. https://doi.org/10.1681/ASN.2010080888