title: SGLT2 inhibitor therapy improves blood glucose but does not prevent diabetic bone disease in diabetic DBA/2J male mice.
abstract: Persons with type 1 and type 2 diabetes have increased fracture risk, attributed to deficits in the microarchitecture and strength of diabetic bone, thought to be mediated, in part, by the consequences of chronic hyperglycemia. Therefore, to examine the effects of a glucose-lowering SGLT2 inhibitor on blood glucose (BG) and bone homeostasis in a model of diabetic bone disease, male DBA/2J mice with or without streptozotocin (STZ)-induced hyperglycemia were fed chow containing the SGLT2 inhibitor, canagliflozin (CANA), or chow without drug, for 10weeks of therapy. Thereafter, serum bone biomarkers were measured, fracture resistance of cortical bone was assessed by μCT analysis and a three-point bending test of the femur, and vertebral bone strength was determined by compression testing. In the femur metaphysis and L6 vertebra, long-term diabetes (DM) induced deficits in trabecular bone microarchitecture. In the femur diaphysis, a decrease in cortical bone area, cortical thickness and minimal moment of inertia occurred in DM (p<0.0001, for all) while cortical porosity was increased (p<0.0001). These DM changes were associated with reduced fracture resistance (decreased material strength and toughness; decreased structural strength and rigidity; p<0.001 for all). Significant increases in PTH (p<0.0001), RatLAPs (p=0.0002), and urine calcium concentration (p<0.0001) were also seen in DM. Canagliflozin treatment improved BG in DM mice by ~35%, but did not improve microarchitectural parameters. Instead, in canagliflozin-treated diabetic mice, a further increase in RatLAPs was evident, possibly suggesting a drug-related intensification of bone resorption. Additionally, detrimental metaphyseal changes were noted in canagliflozin-treated control mice. Hence, diabetic bone disease was not favorably affected by canagliflozin treatment, perhaps due to insufficient glycemic improvement. Instead, in control mice, long-term exposure to SGLT2 inhibition was associated with adverse effects on the trabecular compartment of bone.
authors.affiliation: University of Kentucky Barnstable Brown Diabetes and Obesity 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: University of Kentucky Barnstable Brown Diabetes and Obesity 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
authors.initials: R
authors.lastname: Clay Bunn
authors.affiliation: VA Tennessee Valley Health Care System, Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, Nashville, TN 37232, USA; VA Tennessee Valley Health Care System, Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Jeffry S
authors.initials: JS
authors.lastname: Nyman
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA.
authors.forename: Mallikarjuna R
authors.initials: MR
authors.lastname: Rettiganti
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA.
authors.forename: Gael E
authors.initials: GE
authors.lastname: Cockrell
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Wahl
authors.affiliation: VA Tennessee Valley Health Care System, Department of Orthopaedic Surgery & Rehabilitation, Vanderbilt University Medical Center, Nashville, TN 37232, USA; VA Tennessee Valley Health Care System, Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Sasidhar
authors.initials: S
authors.lastname: Uppuganti
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences and Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA.
authors.forename: Charles K
authors.initials: CK
authors.lastname: Lumpkin
authors.affiliation: University of Kentucky Barnstable Brown Diabetes and Obesity 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; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001847:Bone Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D000068896:Canagliflozin / Q000494:pharmacology / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D001786:Blood Glucose; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D000068896:Canagliflozin
keywords: Canagliflozin; Cortical bone; Diabetic bone disease; Microarchitecture; Trabecular bone; Type 1 diabetes