Dapagliflozin Attenuates Hyperglycemia Related Osteoporosis in ZDF Rats by Alleviating Hypercalciuria

Ji-Yu Wang; Yan-Zhen Cheng; Shuang-Li Yang; Min An; Hua Zhang; Hong Chen; Li Yang

doi:10.3389/fendo.2019.00700

Dapagliflozin Attenuates Hyperglycemia Related Osteoporosis in ZDF Rats by Alleviating Hypercalciuria

Front Endocrinol (Lausanne). 2019 Nov 5:10:700. doi: 10.3389/fendo.2019.00700. eCollection 2019.

Authors

Ji-Yu Wang¹, Yan-Zhen Cheng¹, Shuang-Li Yang^{1

2}, Min An¹, Hua Zhang¹, Hong Chen¹, Li Yang¹

Affiliations

¹ Department of Endocrinology and Metabolism, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
² Department of Endocrinology and Metabolism, The Second Affiliated Hospital of GuiZhou Medical University, Kaili, China.

Abstract

Recent studies showed that in patients with type 2 diabetes mellitus (T2DM), Sodium-dependent glucose transporters 2 inhibitor (SGLT2I) may cause potential adverse effects on the skeleton such as increasing the risk of fracture. This risk is possibly mediated by effects induced by all SGLT2I class drugs, but whether Dapagliflozin aggravates osteoporosis in patients with T2DM remains controversial. Therefore, we designed this study to explore how Dapagliflozin affects the metabolism and the quality of bone in T2DM animal models. The effect of Dapagliflozin on the skeleton was evaluated on male ZDF (Zucker Diabetic Fatty) rats-a rat model of diet induced spontaneous T2DM. Dapagliflozin was administrated via gavage at the dosage of 10 mg/kg/day. Bone tissue mineral density and the microarchitecture of tibiae were measured with micro-CT and biomechanics characteristic of the femora were tested using a three-point bending test. Serum bone biomarkers and other metabolic parameters were also tested via ELISA or other assays. Our results found that diabetic rats demonstrated symptoms of osteoporosis and Dapagliflozin could help to alleviate these defections caused by diabetes. Compared to the negative controls, the serum CT (calcitonin) level in ZDF rats as well as the uric calcium and phosphate levels were elevated, and these symptoms were alleviated by Dapagliflozin. Tibiae of Dapagliflozin treated rats demonstrated decreased cortical tissue mineral density while trabecular tissue mineral density and mean bone mineral density received a rise when compared to the matched controls. ZDF rats also showed defections in femora stiffness which could be relieved by Dapagliflozin administration. The mechanism of Dapagliflozin affecting bone quality is possibly connected to the suppression of serum calcitonin and excretion of calcium via urine rose by hyperglycemia. In conclusion, Dapagliflozin can prevent osteoporosis in ZDF rats by alleviating hypercalciuria.

Keywords: Sodium dependent glucose transporters 2 inhibitor; ZDF rats; bone microarchitecture; dapagliflozin; type 2 diabetes mellitus.