The impact of SGLT2 inhibitors, compared with insulin, on diabetic bone disease in a mouse model of type 1 diabetes
| Autor: | Kathryn M. Thrailkill, Katherine L. Thompson, R. Clay Bunn, Sasidhar Uppuganti, Jeffry S. Nyman, Charles K. Lumpkin, John L. Fowlkes, Evangelia Kalaitzoglou |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Blood Glucose Male medicine.medical_specialty Histology Bone disease Physiology Endocrinology Diabetes and Metabolism medicine.medical_treatment 030209 endocrinology & metabolism Bone and Bones Article Bone remodeling 03 medical and health sciences 0302 clinical medicine Sodium-Glucose Transporter 2 Internal medicine medicine Animals Insulin Bone Resorption Canagliflozin Sodium-Glucose Transporter 2 Inhibitors Bone mineral Type 1 diabetes business.industry Streptozotocin medicine.disease Bone Diseases Metabolic Disease Models Animal Fibroblast Growth Factor-23 030104 developmental biology medicine.anatomical_structure Endocrinology Diabetes Mellitus Type 1 Phenotype Mice Inbred DBA Linear Models Cortical bone business Biomarkers medicine.drug |
| Zdroj: | Bone. 94 |
| ISSN: | 1873-2763 |
| Popis: | Skeletal co-morbidities in type 1 diabetes include an increased risk for fracture and delayed fracture healing, which are intertwined with disease duration and the presence of other diabetic complications. As such, chronic hyperglycemia is undoubtedly a major contributor to these outcomes, despite standard insulin-replacement therapy. Therefore, using the streptozotocin (STZ)-induced model of hypoinsulinemic hyperglycemia in DBA/2J male mice, we compared the effects of two glucose lowering therapies on the fracture resistance of bone and markers of bone turnover. Twelve week-old diabetic (DM) mice were treated for 9 weeks with: 1) oral canagliflozin (CANA, dose range ~10-16 mg/kg/day), an inhibitor of the renal sodium-dependent glucose co-transporter type 2 (SGLT2); 2) subcutaneous insulin, via minipump (INS, 0.125 units/day); 3) co-therapy (CANA + INS); or 4) no treatment (STZ, without therapy). These groups were also compared to non-diabetic control groups. Untreated diabetic mice experienced increased bone resorption and significant deficits in cortical and trabecular bone that contributed to structural weakness of the femur mid-shaft and the lumbar vertebra, as determined by three-point bending and compression tests, respectively. Treatment with either canagliflozin or insulin alone only partially rectified hyperglycemia and the diabetic bone phenotype. However, when used in combination, normalization of glycemic control was achieved, and a prevention of the DM-related deterioration in bone microarchitecture and bone strength occurred, due to additive effects of canagliflozin and insulin. Nevertheless, CANA-treated mice, whether diabetic or non-diabetic, demonstrated an increase in urinary calcium loss; FGF23 was also increased in CANA-treated DM mice. These findings could herald ongoing bone mineral losses following CANA exposure, suggesting that certain CANA-induced skeletal consequences might detract from therapeutic improvements in glycemic control, as they relate to diabetic bone disease. |
| Databáze: | OpenAIRE |
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