title: The impact of SGLT2 inhibitors, compared with insulin, on diabetic bone disease in a mouse model of type 1 diabetes.
abstract: 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 9weeks with: 1) oral canagliflozin (CANA, dose range ~10-16mg/kg/day), an inhibitor of the renal sodium-dependent glucose co-transporter type 2 (SGLT2); 2) subcutaneous insulin, via minipump (INS, 0.125units/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.
authors.affiliation: University of Kentucky Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536, USA. Electronic address: kathryn.thrailkill@uky.edu.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Thrailkill
authors.affiliation: VA Tennessee Valley Health Care System, University Medical Center, Nashville, TN 37232, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Nyman
authors.affiliation: University of Kentucky Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: R Clay
authors.initials: RC
authors.lastname: Bunn
authors.affiliation: VA Tennessee Valley Health Care System, University Medical Center, Nashville, TN 37232, USA; Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Sasidhar
authors.initials: S
authors.lastname: Uppuganti
authors.affiliation: Department of Statistics, University of Kentucky, Lexington, KY 40536, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Thompson
authors.affiliation: (g)Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, 72202, USA.
authors.forename: Charles K
authors.initials: CK
authors.lastname: Lumpkin
authors.affiliation: University of Kentucky Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Kalaitzoglou
authors.affiliation: University of Kentucky Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA; Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Fowlkes
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001851:Bone Diseases, Metabolic / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D001862:Bone Resorption / Q000097:blood / Q000150:complications / Q000473:pathology; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D000068896:Canagliflozin / Q000494:pharmacology / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D000089703:Fibroblast Growth Factor-23; D007328:Insulin / Q000494:pharmacology / Q000627:therapeutic use*; D016014:Linear Models; D008297:Male; D008811:Mice, Inbred DBA; D010641:Phenotype; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; C000717428:Fgf23 protein, mouse; D007328:Insulin; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin; D000089703:Fibroblast Growth Factor-23
keywords: Bone microarchitecture; Canagliflozin; Cortical bone; Dapagliflozin; Glycosuria; Hypercalciuria; Trabecular bone