Canagliflozin, an SGLT2 inhibitor, corrects glycemic dysregulation in TallyHO model of T2D but only partially prevents bone deficits

Kathryn M. Thrailkill, R. Clay Bunn, Sasidhar Uppuganti, Philip Ray, Iuliana Popescu, Evangelia Kalaitzoglou, John L. Fowlkes, Jeffry S. Nyman

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Higher fracture risk in type 2 diabetes (T2D) is attributed to disease-specific deficits in micro-structural and material properties of bone, although the primary cause is not yet established. The TallyHO (TH) mouse is a polygenic model of early-onset T2D and obesity analogous to adolescent-onset T2D in humans. Due to incomplete penetrance of the phenotype, ~25% of male TH mice never develop hyperglycemia, providing a strain-matched, non-diabetic control. Utilizing this model of T2D, we examined the impact of glucose-lowering therapy with canagliflozin (CANA) on diabetic bone. Male TH mice with or without hyperglycemia (High BG, Low BG) were monitored from ~8 to 20 weeks of age, and compared to age-matched, male, TH mice treated with CANA from ~8 to 20 weeks of age. At 20 weeks, untreated TH mice with high BG [High BG: 687 ± 106 mg/dL] exhibited lower body mass, decrements in cortical bone of the femur (decreased cross-sectional area and thickness; increased porosity) and in trabecular bone of the femur metaphysis and L6 vertebra (decreased bone volume fraction, thickness, and tissue mineral density), as well as decrements in cortical and vertebral bone strength (decreased yield force and ultimate force) when compared to untreated TH mice with low BG [Low BG: 290 ± 98 mg/dL; p < 0.0001]. CANA treatment was metabolically advantageous, normalizing body mass, BG and HbA1c to values comparable to the Low BG group. With drug-induced glycemic improvement, cortical area and thickness were significantly higher in the CANA than in the High BG group, but deficits in strength persisted with lower yield force and yield stress (partially independent of bone geometry) in the CANA group. Additionally, CANA only partially prevented the T2D-related loss in trabecular bone volume fraction. Taken together, these findings suggest that the ability of CANA to lower glucose and normalized glycemic control ameliorates diabetic bone disease but not fully.

Original languageEnglish
Article number115625
JournalBone
Volume141
DOIs
StatePublished - Dec 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 1I01BX004297 (to J.S.N.). Additional funding was provided by the University of Kentucky Barnstable Brown Diabetes Center Endowment. The authors have no conflict of interest to declare.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 1I01BX004297 (to J.S.N.). Additional funding was provided by the University of Kentucky Barnstable Brown Diabetes Center.

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 1I01BX004297 (to J.S.N.). Additional funding was provided by the University of Kentucky Barnstable Brown Diabetes Center Endowment. The authors have no conflict of interest to declare.

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 1I01BX004297 (to J.S.N.). Additional funding was provided by the University of Kentucky Barnstable Brown Diabetes Center.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

  • Animal models
  • Bone microarchitecture
  • Bone μCT
  • Canagliflozin
  • Fracture
  • Phosphate wasting
  • Type 2 diabetes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Histology
  • Physiology

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