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

doi:10.1016/j.bone.2020.115625

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 journal › Article › peer-review

12 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 language	English
Article number	115625
Journal	Bone
Volume	141
DOIs	https://doi.org/10.1016/j.bone.2020.115625
State	Published - Dec 2020

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.

Funding

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. 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.

Funders	Funder number
University of Kentucky Barnstable-Brown Diabetes Center
University of Kentucky Barnstable Brown Diabetes Center Research Endowment
Veterans Health Administration
National Institutes of Health (NIH)	R56DK084045
National Institute of Arthritis and Musculoskeletal and Skin Diseases	R21AR070620
U.S. Department of Veterans Affairs
VA Office of Research and Development	1I01BX004297
Health Services Research and Development Center for Mental Health Outcomes Research

Keywords

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

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Histology
Physiology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bone.2020.115625

Cite this

@article{84c23b4ecc924c818178b72cb4176bff,

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

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.",

keywords = "Animal models, Bone microarchitecture, Bone μCT, Canagliflozin, Fracture, Phosphate wasting, Type 2 diabetes",

author = "Thrailkill, {Kathryn M.} and Bunn, {R. Clay} and Sasidhar Uppuganti and Philip Ray and Iuliana Popescu and Evangelia Kalaitzoglou and Fowlkes, {John L.} and Nyman, {Jeffry S.}",

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doi = "10.1016/j.bone.2020.115625",

language = "English",

volume = "141",

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T1 - Canagliflozin, an SGLT2 inhibitor, corrects glycemic dysregulation in TallyHO model of T2D but only partially prevents bone deficits

AU - Thrailkill, Kathryn M.

AU - Bunn, R. Clay

AU - Uppuganti, Sasidhar

AU - Ray, Philip

AU - Popescu, Iuliana

AU - Kalaitzoglou, Evangelia

AU - Fowlkes, John L.

AU - Nyman, Jeffry S.

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

KW - Animal models

KW - Bone microarchitecture

KW - Bone μCT

KW - Canagliflozin

KW - Fracture

KW - Phosphate wasting

KW - Type 2 diabetes

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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