2型糖尿病(T2D)增加骨折发生率和骨折相关死亡率(KK。Cg-Ay/J.杰克逊实验室;可从以下网址获得:https://www.jax.org/strain/002468)。虽然存在许多用于T2D的鼠标模型,很少能有效刺激男女持续高血糖,甚至更少适合骨骼研究。常用的模型,如db/db和ob/ob改变了瘦素途径,混杂骨相关的发现,因为瘦素调节骨特性(Fajardo等人。“骨与矿物研究杂志”29(5):1025-1040,2014)。黄色KuoKondo(KK/Ay)鼠标,T2D的多基因突变模型,能够在两种性别中产生一致的糖尿病状态,并解决了缺乏用于骨骼研究的T2D模型的问题。KK/Ay的糖尿病状态源于agouti基因的突变,负责小鼠的皮毛颜色。这种突变诱导不同组织类型的异位基因表达,导致具有黄色皮毛的糖尿病小鼠(Moussa和Claycombe在肥胖研究7(5):506-514,1999)。雄性和雌性KK/Ay小鼠表现出持续性高血糖,将其定义为血糖(BG)水平始终超过300mg/dL的糖尿病患者。值得注意的是,这项研究中的雄性对照小鼠也患有糖尿病,提出了一个重大的限制。然而,雄性和雌性KK/Ay小鼠显示出显著升高的BG水平,HbA1c,和血清胰岛素浓度与非糖尿病雌性对照小鼠相比。早期T2D的特点是由细胞胰岛素抵抗引起的高血糖和高胰岛素血症。而后期可能以β细胞凋亡导致的低胰岛素血症为特征(Banday等人。阿维森纳医学杂志10(04):174-188,2020年和克莱因等人。细胞代谢34(1):11-20,2022)。观察到的高血糖,高胰岛素血症,并且β细胞质量没有差异表明本研究中的KK/Ay小鼠正在对T2D的早期阶段进行建模。虽然在这项研究中观察到骨骼微结构受损,较老的KK/Ay小鼠,代表T2D的更高级阶段,可能表现出更明显的骨骼表现。与对照组相比,KK/Ay小鼠股骨有较高的皮质面积和皮质厚度,和改善的小梁性能,这通常表明更大的骨强度。然而,KK/Ay小鼠在两种性别中均显示出较低的皮质组织矿物质密度,而在雌性中显示出增加的皮质孔隙率。与对照组相比,KK/Ay小鼠的股骨骨折不稳定韧性总体较低。这些发现表明,在KK/Ay小鼠的股骨中注意到的机械完整性降低可能是由于整体骨质量受损。
Type 2 diabetes (T2D) increases fracture incidence and fracture-related mortality rates (KK.Cg-Ay/J. The Jackson Laboratory; Available from: https://www.jax.org/strain/002468 ). While numerous mouse models for T2D exist, few effectively stimulate persistent hyperglycemia in both sexes, and even fewer are suitable for bone studies. Commonly used models like db/db and ob/ob have altered leptin pathways, confounding bone-related findings since leptin regulates bone properties (Fajardo et al. in Journal of Bone and Mineral Research 29(5): 1025-1040, 2014). The Yellow Kuo Kondo (KK/Ay) mouse, a polygenic mutation model of T2D, is able to produce a consistent diabetic state in both sexes and addresses the lack of a suitable model of T2D for bone studies. The diabetic state of KK/Ay stems from a mutation in the agouti gene, responsible for coat color in mice. This mutation induces ectopic gene expression across various tissue types, resulting in diabetic mice with yellow fur coats (Moussa and Claycombe in Obesity Research 7(5): 506-514, 1999). Male and female KK/Ay mice exhibited persistent hyperglycemia, defining them as diabetic with blood glucose (BG) levels consistently exceeding 300 mg/dL. Notably, male control mice in this study were also diabetic, presenting a significant limitation. Nevertheless, male and female KK/Ay mice showed significantly elevated BG levels, HbA1c, and serum insulin concentration when compared to the non-diabetic female control mice. Early stages of T2D are characterized by hyperglycemia and hyperinsulinemia resulting from cellular insulin resistance, whereas later stages may feature hypoinsulinemia due to β-cell apoptosis (Banday et al. Avicenna Journal of Medicine 10(04): 174-188, 2020 and Klein et al. Cell Metabolism 34(1): 11-20, 2022). The observed hyperglycemia, hyperinsulinemia, and the absence of differences in β-cell mass suggest that KK/Ay mice in this study are modeling the earlier stages of T2D. While compromised bone microarchitecture was observed in this study, older KK/Ay mice, representing more advanced stages of T2D, might exhibit more pronounced skeletal manifestations. Compared to the control group, the femora of KK/Ay mice had higher cortical area and cortical thickness, and improved trabecular properties which would typically be indicative of greater bone strength. However, KK/Ay mice displayed lower cortical tissue mineral density in both sexes and increased cortical porosity in females. Fracture instability toughness of the femora was lower in KK/Ay mice overall compared to controls. These findings indicate that decreased mechanical integrity noted in the femora of KK/Ay mice was likely due to overall bone quality being compromised.