Genetic ablation of SGLT2 function in mice impairs tissue mineral density but does not affect fracture resistance of bone

Kathryn M. Thrailkill, R. Clay Bunn, Sasidhar Uppuganti, Philip Ray, Kate Garrett, Iuliana Popescu, Jacquelyn S. Pennings, John L. Fowlkes, Jeffry S. Nyman

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Selective sodium-dependent glucose co-transporter 2 inhibitors (SGLT2Is) are oral hypoglycemic medications utilized increasingly in the medical management of hyperglycemia among persons with type 2 diabetes (T2D). Despite favorable effects on cardiovascular events, specific SGLT2Is have been associated with an increased risk for atypical fracture and amputation in subgroups of the T2D population, a population that already has a higher risk for typical fragility fractures than the general population. To better understand the effect of SGLT2 blockade on skeletal integrity, independent of diabetes and its co-morbidities, we utilized the “Jimbee” mouse model of slc5a2 gene mutation to investigate the impact of lifelong SGLT2 loss-of-function on metabolic and skeletal phenotype. Jimbee mice maintained normal glucose homeostasis, but exhibited chronic polyuria, glucosuria and hypercalciuria. The Jimbee mutation negatively impacted appendicular growth of the femur and resulted in lower tissue mineral density of both cortical and trabecular bone of the femur mid-shaft and distal femur metaphysis, respectively. Several components of the Jimbee phenotype were characteristic only of male mice compared with female mice, including reductions: in body weight; in cortical area of the mid-shaft; and in trabecular thickness within the metaphysis. Despite these decrements, the strength of femur diaphysis in bending (cortical bone), which increased with age, and the strength of L6 vertebra in compression (primarily trabecular bone), which decreased with age, were not affected by the mutation. Moreover, the age-related decline in bone toughness was less for Jimbee mice, compared with control mice, such that by 49–50 weeks of age, Jimbee mice had significantly tougher femurs in bending than C57BL/6J mice. These results suggest that chronic blockade of SGLT2 in this model reduces the mineralization of bone but does not reduce its fracture resistance.

Original languageEnglish
Article number115254
JournalBone
Volume133
DOIs
StatePublished - Apr 2020

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Grants, R21AR070620 (to K.M.T and J.S.N.) and R56DK084045 (to J.L.F.), as well as the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development 1I01BX001018 (to J.S.N.). Additional funding was provided by the University of Kentucky Barnstable Brown Diabetes Center Endowment. The mouse strain used for this research project, C57BL/6J-Slc5a2m1Btlr/Mmmh, RRID: MMRRC_036517-MU, was obtained from the Mutant Mouse Resource and Research Center (MMRRC) at University of Missouri, an NIH-funded strain repository, and was donated to the MMRRC by Bruce Beutler, M.D. University of Texas Southwestern Medical Center. The authors also appreciate the preliminary statistical analysis of portions of this data provided by Katherine L. Thompson, PhD and Gregory S. Hawk, BS from the University Of Kentucky Department Of Statistics. This work was supported by grants from the National Institutes of Health, R21AR070620 (to K.M.T and J.S.N.) and R56DK084045 (to J.L.F.); as well as the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, 1I01BX001018 (to J.S.N.). Additional funding was provided by the University of Kentucky Barnstable Brown Diabetes Center Research Endowment. K.M.T. R.C.B. J.S.N. I.P. and J.L.F. contributed to study conceptualization. K.M.T. R.C.B. J.S.N. S.U. P.R. K.G. I.P. and J.L.F. contributed to investigation and data curation, and to the writing, review and editing of the manuscript. J.S.N. J.S.P, and K.M.T. provided statistical analysis and interpretation of the data, and accept responsibility for the integrity of the data analysis. K.M.T. J.S.N. and J.L.F. contributed to funding acquisition. All authors have approved the final version of the submitted manuscript. The authors have no financial or personal conflicts of interest to disclose.

Funding Information:
This work was supported by National Institutes of Health Grants, R21AR070620 (to K.M.T and J.S.N.) and R56DK084045 (to J.L.F.), as well as the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development 1I01BX001018 (to J.S.N.). Additional funding was provided by the University of Kentucky Barnstable Brown Diabetes Center Endowment. The mouse strain used for this research project, C57BL/6J-Slc5a2m1Btlr/Mmmh, RRID: MMRRC_036517-MU, was obtained from the Mutant Mouse Resource and Research Center (MMRRC) at University of Missouri, an NIH-funded strain repository, and was donated to the MMRRC by Bruce Beutler, M.D., University of Texas Southwestern Medical Center. The authors also appreciate the preliminary statistical analysis of portions of this data provided by Katherine L. Thompson, PhD and Gregory S. Hawk, BS from the University Of Kentucky Department Of Statistics.

Funding Information:
This work was supported by grants from the National Institutes of Health , R21AR070620 (to K.M.T and J.S.N.) and R56DK084045 (to J.L.F.); as well as the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development , 1I01BX001018 (to J.S.N.). Additional funding was provided by the University of Kentucky Barnstable Brown Diabetes Center Research Endowment.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • Bone microarchitecture
  • Canagliflozin
  • Cortical bone
  • Fracture
  • Jimbee mouse
  • Proximal tubule
  • Trabecular bone

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Histology
  • Physiology

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