Genetic ablation of SGLT2 function in mice impairs tissue mineral density but does not affect fracture resistance of bone.
Genetic ablation of SGLT2 function in mice impairs tissue mineral density but does not affect fracture resistance of bone.
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DOI：
10.1016/j.bone.2020.115254
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发表时间：
2020-01
期刊：
影响因子：
4.1
通讯作者：
K. Thrailkill;R. C. Bunn;S. Uppuganti;Philip D. Ray;Kate Garrett;I. Popescu;J. Pennings;J. Fowlkes;J. Nyman
中科院分区：
文献类型：
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作者：
K. Thrailkill;R. C. Bunn;S. Uppuganti;Philip D. Ray;Kate Garrett;I. Popescu;J. Pennings;J. Fowlkes;J. Nyman
选择性钠依赖性葡萄糖共转运蛋白2抑制剂（SGLT2Is）是口服降糖药物，越来越多地用于2型糖尿病（T2D）患者高血糖的医疗管理。尽管对心血管事件有良好的影响，但在T2D人群的亚组中，特定的SGLT2Is与非典型骨折和截肢的风险增加有关，而T2D人群发生典型脆性骨折的风险已经高于一般人群。为了更好地了解SGLT2阻断对骨骼完整性的影响，独立于糖尿病及其合病，我们利用slc5a2基因突变的“Jimbee”小鼠模型来研究终身SGLT2功能丧失对代谢和骨骼表型的影响。Jimbee小鼠维持正常的葡萄糖稳态，但表现出慢性多尿、糖尿和高钙尿。Jimbee突变对股骨阑尾生长产生负面影响，导致股骨中干和股骨远端干骺端皮质骨和小梁骨的组织矿物质密度降低。与雌性小鼠相比，金比表型的几个组成部分仅具有雄性小鼠的特征，包括体重减轻；中轴皮质区；以及干骺端小梁的厚度。尽管有这些下降，但弯曲股骨骨干（皮质骨）的强度随年龄增长而增加，L6椎体受压（主要是小梁骨）的强度随年龄增长而下降，但不受突变的影响。此外，与对照小鼠相比，Jimbee小鼠与年龄相关的骨韧性下降较少，因此在49-50周龄时，Jimbee小鼠的弯曲股骨明显比C57BL/6J小鼠更坚韧。这些结果表明，在该模型中，慢性阻断SGLT2可减少骨矿化，但不降低其抗骨折性。
Selective sodium-dependent glucose co-transporter 2 inhibitors (SGLT2Is) are oral hypoglycemic medications utilized increasingly in the medical management of hyperglycemia among persons with type 2 diabetes (T2D). Despite favorable effects on cardiovascular events, specific SGLT2Is have been associated with an increased risk for atypical fracture and amputation in subgroups of the T2D population, a population that already has a higher risk for typical fragility fractures than the general population. To better understand the effect of SGLT2 blockade on skeletal integrity, independent of diabetes and its co-morbidities, we utilized the “Jimbee” mouse model ofslc5a2gene mutation to investigate the impact of lifelong SGLT2 loss-of-function on metabolic and skeletal phenotype. Jimbee mice maintained normal glucose homeostasis, but exhibited chronic polyuria, glucosuria and hypercalciuria. The Jimbee mutation negatively impacted appendicular growth of the femur and resulted in lower tissue mineral density of both cortical and trabecular bone of the femur mid-shaft and distal femur metaphysis, respectively. Several components of the Jimbee phenotype were characteristic only of male mice compared with female mice, including reductions: in body weight; in cortical area of the mid-shaft; and in trabecular thickness within the metaphysis. Despite these decrements, the strength of femur diaphysis in bending (cortical bone), which increased with age, and the strength of L6 vertebra in compression (primarily trabecular bone), which decreased with age, were not affected by the mutation. Moreover, the age-related decline in bone toughness was less for Jimbee mice, compared with control mice, such that by 49–50 weeks of age, Jimbee mice had significantly tougher femurs in bending than C57BL/6J mice. These results suggest that chronic blockade of SGLT2 in this model reduces the mineralization of bone but does not reduce its fracture resistance.