Skeletal manifestations in a streptozotocin-induced C57BL/6 model of Type 1 diabetes.
Skeletal manifestations in a streptozotocin-induced C57BL/6 model of Type 1 diabetes.
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DOI：
10.1016/j.bonr.2022.101609
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发表时间：
2022-12
期刊：
影响因子：
2.5
通讯作者：
Wallace, Joseph M.
中科院分区：
文献类型：
--
作者：
Hatch, Jennifer M.;Segvich, Dyann M.;Kohler, Rachel;Wallace, Joseph M.
糖尿病是一种代谢性疾病，它深刻地影响着身体的许多器官系统，包括骨骼。就像生物学中经常出现的情况一样，在考虑骨骼发育、疾病进展和结果时，性别之间存在固有的差异。因此，本研究的目的是开发一种使用链脲佐菌素(STZ)在C57BL/6小鼠中可靠地诱导两性糖尿病的方案，并对所产生的骨表型进行表征。我们推测，链脲佐菌素对胰岛β细胞的破坏将导致糖尿病状态，并伴有下游骨骼表现。从8周大的小鼠开始，连续5天注射STZ(雄性65 mg/kg，雌性90 mg/kg)，溶解在柠檬酸缓冲液中。对小鼠的糖尿病状态进行了5周的监测，以确保持续的高血糖，并在15周大的时候对小鼠实施安乐死。糖尿病通过血糖监测、血糖和胰岛素耐量测试、糖化血红蛋白测定和胰腺组织学染色确诊。使用微型计算机断层扫描来评估骨结构，并使用全骨力学测试来评估骨功能的完整性，来表征由此产生的骨表型。无论男女，小鼠都经历了β细胞质量的丧失和血红蛋白糖基化的增加，以及骨小梁厚度和骨小梁组织矿物质密度的减少，以及皮质厚度和皮质骨面积分数的减少。在雌性小鼠中，改变面积比例是由整体骨骼大小的减少驱动的，而在雄性小鼠中，变化是由增加的骨髓面积驱动的。男性也经历了皮质TMD的降低。胫骨的机械弯曲测试显示，女性胫骨的屈服力和极限力减少，导致屈服功和总功降低，刚度减少约40%。当使用梁理论估计组织水平参数时，屈服和极限应力以及弹性模数显著降低。先前报道的STZ对小鼠动物作用的机制相似，以及通过IP注射STZ的简便性，使该模型成为未来探索骨质疏松性骨病、糖尿病以及雌激素和葡萄糖敏感性之间联系的有力候选者。
Diabetes Mellitus is a metabolic disease which profoundly affects many organ systems in the body, including the skeleton. As is often the case with biology, there are inherent differences between the sexes when considering skeletal development and disease progression and outcome. Therefore, the aim of this study was to develop a protocol to reliably induce diabetes in both sexes of the C57BL/6 mouse utilizing streptozotocin (STZ) and to characterize the resulting bone phenotype. We hypothesized that destruction of the β-cells in the pancreatic islet by STZ would result in a diabetic state with downstream skeletal manifestations. Beginning at 8 weeks of age, mice were injected for 5 consecutive days with STZ (65 mg/kg males, 90 mg/kg females) dissolved in a citrate buffer. The diabetic state of the mice was monitored for 5 weeks to ensure persistent hyperglycemia and mice were euthanized at 15 weeks of age. Diabetes was confirmed through blood glucose monitoring, glucose and insulin tolerance testing, HbA1c measurement, and histological staining of the pancreas. The resulting bone phenotype was characterized using microcomputed tomography to assess bone structure, and whole bone mechanical testing to assess bone functional integrity. Mice from both sexes experienced loss of β-cell mass and increased glycation of hemoglobin, as well as reduced trabecular thickness and trabecular tissues mineral density (TMD), and reduced cortical thickness and cortical bone area fraction. In female mice the change area fraction was driven by a reduction in overall bone size while in male mice, the change was driven by increased marrow area. Males also experienced reduced cortical TMD. Mechanical bending tests of the tibiae showed significant results in females with a reduction in yield force and ultimate force driving lower work to yield and total work and a roughly 40 % reduction of stiffness. When tissue level parameters were estimated using beam theory, there was a significant reduction in yield and ultimate stresses as well as elastic modulus. The previously reported mechanistic similarity in the action of STZ on murine animals, as well as the ease of STZ administration via IP injection make this model is a strong candidate for future exploration of osteoporotic bone disease, Diabetes Mellitus, and the link between estrogen and glucose sensitivity.
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