University of Kentucky Barnstable Brown Diabetes Center and the Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America.
University of Kentucky Barnstable Brown Diabetes Center and the Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY 40536, United States of America.
Bone. 2020 Dec;141:115625. doi: 10.1016/j.bone.2020.115625. Epub 2020 Sep 2.
Higher fracture risk in type 2 diabetes (T2D) is attributed to disease-specific deficits in micro-structural and material properties of bone, although the primary cause is not yet established. The TallyHO (TH) mouse is a polygenic model of early-onset T2D and obesity analogous to adolescent-onset T2D in humans. Due to incomplete penetrance of the phenotype, ~25% of male TH mice never develop hyperglycemia, providing a strain-matched, non-diabetic control. Utilizing this model of T2D, we examined the impact of glucose-lowering therapy with canagliflozin (CANA) on diabetic bone. Male TH mice with or without hyperglycemia (High BG, Low BG) were monitored from ~8 to 20 weeks of age, and compared to age-matched, male, TH mice treated with CANA from ~8 to 20 weeks of age. At 20 weeks, untreated TH mice with high BG [High BG: 687 ± 106 mg/dL] exhibited lower body mass, decrements in cortical bone of the femur (decreased cross-sectional area and thickness; increased porosity) and in trabecular bone of the femur metaphysis and L6 vertebra (decreased bone volume fraction, thickness, and tissue mineral density), as well as decrements in cortical and vertebral bone strength (decreased yield force and ultimate force) when compared to untreated TH mice with low BG [Low BG: 290 ± 98 mg/dL; p < 0.0001]. CANA treatment was metabolically advantageous, normalizing body mass, BG and HbA1c to values comparable to the Low BG group. With drug-induced glycemic improvement, cortical area and thickness were significantly higher in the CANA than in the High BG group, but deficits in strength persisted with lower yield force and yield stress (partially independent of bone geometry) in the CANA group. Additionally, CANA only partially prevented the T2D-related loss in trabecular bone volume fraction. Taken together, these findings suggest that the ability of CANA to lower glucose and normalized glycemic control ameliorates diabetic bone disease but not fully.
2 型糖尿病（T2D）患者骨折风险较高，这归因于骨微观结构和材料特性的疾病特异性缺陷，尽管其主要病因尚未确定。TallyHO（TH）小鼠是一种多基因模型，模拟了人类青少年起病的 2 型糖尿病和肥胖。由于表型的不完全外显，约 25%的雄性 TH 小鼠从不发生高血糖，为其提供了一种与糖尿病相匹配的非糖尿病对照。利用这种 2 型糖尿病模型，我们研究了用坎格列净（CANA）降低血糖治疗对糖尿病骨的影响。雄性 TH 小鼠无论是否伴有高血糖（高 BG、低 BG），均从 8 至 20 周龄进行监测，并与 8 至 20 周龄接受 CANA 治疗的同年龄雄性 TH 小鼠进行比较。20 周时，未经治疗的高血糖 TH 小鼠（高 BG：687±106mg/dL）表现出较低的体重，股骨皮质骨（横截面积和厚度减小；骨孔隙度增加）和股骨干骺端及 L6 椎体的松质骨（骨体积分数、厚度和组织矿物质密度减小）减少，以及皮质骨和椎体骨强度降低（屈服力和最大力减小），与未经治疗的低血糖 TH 小鼠（低 BG：290±98mg/dL；p<0.0001）相比。CANA 治疗在代谢方面具有优势，可将体重、血糖和糖化血红蛋白（HbA1c）正常化至与低 BG 组相当的水平。随着药物诱导的血糖改善，CANA 组的皮质面积和厚度显著高于高 BG 组，但在 CANA 组，屈服力和屈服应力仍存在缺陷（部分独立于骨几何形状）。此外，CANA 仅部分预防了 2 型糖尿病相关的骨小梁体积分数丢失。总之，这些发现表明，CANA 降低血糖和正常血糖控制的能力改善了糖尿病性骨病，但并非完全如此。
