Groupe Etude Remodelage Osseux et biomatériaux, GEROM, UPRES EA 4658, SFR ICAT 4208, Institut de Biologie en Santé, UNIV Angers, 4 rue larrey, 49933, Angers Cedex 09, France.
School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
Calcif Tissue Int. 2020 Sep;107(3):281-293. doi: 10.1007/s00223-020-00720-4. Epub 2020 Jul 8.
The aim of this study is to compare head-to-head the effects of dapagliflozin and liraglutide on bone strength and bone material properties in a pre-clinical model of diabetes-obesity. Combined low-dose streptozotocin and high fat feeding were employed in mice to promote obesity, insulin resistance, and hyperglycaemia. Mice were administered daily for 28 days with saline vehicle, 1 mg/kg dapagliflozin or 25 nmol/kg liraglutide. Bone strength was assessed by three-point bending and nanoindentation. Bone material properties were investigated by Fourier transform infrared microspectroscopy/imaging. Although diabetic controls presented with dramatic reductions in mechanical strength, no deterioration of bone microarchitecture was apparent. At the tissue level, significant alterations in phosphate/amide ratio, carbonate/phosphate ratio, tissue water content, crystal size index, collagen maturity and collagen glycation were observed and linked to alteration of matrix biomechanics. Dapagliflozin and liraglutide failed to improve bone strength by 3-point bending or bone microarchitecture during the 28-day-treatment period. At bone formation site, dapagliflozin enhanced phosphate/amide ratio, mineral maturity, and reduced tissue water content, crystal size index, and collagen glycation. Liraglutide had significant effects on phosphate/amide ratio, tissue water content, crystal size index, mature collagen crosslinks, collagen maturity, and collagen glycation. At bone formation site, both drugs modulated matrix biomechanics. This study highlighted that these two molecules are effective in improving bone material properties and modulating matrix biomechanics at bone formation site. This study also highlighted that the resulting effects on bone material properties are not identical between dapagliflozin and liraglutide and not only mediated by lower blood glucose.
本研究旨在比较达格列净和利拉鲁肽在肥胖型糖尿病前临床模型中对骨强度和骨材料特性的影响。采用小剂量链脲佐菌素和高脂饮食联合作用于小鼠，以促进肥胖、胰岛素抵抗和高血糖的发生。给予小鼠每日腹腔注射生理盐水、1mg/kg 达格列净或 25nmol/kg 利拉鲁肽，连续 28 天。通过三点弯曲和纳米压痕法评估骨强度，通过傅里叶变换红外显微光谱/成像技术研究骨材料特性。尽管糖尿病对照组的机械强度显著降低，但骨微结构未见明显恶化。在组织水平上，观察到磷酸盐/酰胺比、碳酸盐/磷酸盐比、组织含水量、晶体尺寸指数、胶原成熟度和胶原糖化的显著变化，并与基质生物力学的改变相关。达格列净和利拉鲁肽在 28 天治疗期间未能改善三点弯曲或骨微结构的骨强度。在骨形成部位，达格列净增加了磷酸盐/酰胺比、矿化成熟度，降低了组织含水量、晶体尺寸指数和胶原糖化。利拉鲁肽对磷酸盐/酰胺比、组织含水量、晶体尺寸指数、成熟胶原交联、胶原成熟度和胶原糖化有显著影响。在骨形成部位，两种药物均调节了基质生物力学。本研究强调，这两种分子可有效改善骨材料特性，并调节骨形成部位的基质生物力学。本研究还强调，达格列净和利拉鲁肽对骨材料特性的影响并不相同，并且不仅仅通过降低血糖来介导。
