Changes in the Fracture Resistance of Bone with the Progression of Type 2 Diabetes in the ZDSD Rat.
Changes in the Fracture Resistance of Bone with the Progression of Type 2 Diabetes in the ZDSD Rat.
复制标题
DOI：
10.1007/s00223-016-0149-z
复制
发表时间：
2016-09
影响因子：
4.2
通讯作者：
Nyman JS
中科院分区：
文献类型：
--
作者：
Creecy A;Uppuganti S;Merkel AR;O'Neal D;Makowski AJ;Granke M;Voziyan P;Nyman JS
与非糖尿病患者相比，2 型糖尿病 (T2D) 患者的骨折风险较高，尽管其面积骨矿物质密度正常或较高。确定糖尿病降低抗骨折能力的机制需要具有良好特征的糖尿病骨病啮齿动物模型。为此，我们假设 ZDSD 大鼠的骨韧性比骨强度随着糖尿病病程的延长而降低。在16周（高血糖发生前）、22周（高血糖5-6周）和29周（高血糖12-13周）时从雄性CD（SD）对照大鼠和雄性ZDSD大鼠中采集骨骼。每个年龄组每个品系至少有 12 只大鼠。 16 周时，2 组大鼠的体重或血糖水平没有差异。将所有大鼠改为 48% kcal 来自脂肪的饮食后 2 周内，只有 ZDSD 大鼠出现高血糖（>250 mg/dl）。他们还在 21 周时开始减轻体重。 CD(SD) 大鼠在高脂肪饮食下仍保持正常血糖 (<110 mg/dl)，并变得肥胖 (>600 g)。根据对腰椎和股骨远端的微计算机断层扫描 (μCT) 分析，非糖尿病大鼠的骨小梁体积不随年龄变化，但在 29 周时低于糖尿病大鼠的 16 周或 22 周。与该发现一致，在高血糖约 12 周后，ZDSD 的 µCT 衍生皮质内孔隙度（股骨骨干）高于年龄匹配的 CD(SD) 大鼠。尽管两种大鼠品系（μCT 和拉曼光谱）的矿化度均与年龄相关，但只有非糖尿病 CD(SD) 大鼠的皮质骨材料强度（来自三点弯曲测试）随着年龄的增长而增加。此外，ZDSD 大鼠的另外两种材料特性，即韧性（半径）和断裂韧性（股骨），随着 T2D 持续时间的延长而显着下降。这伴随着戊糖素（股骨）水平的增加。然而，在任何时间点，糖尿病患者骨骼中的戊糖素均不显着高于非糖尿病患者骨骼。 ZDSD 大鼠具有正常的瘦素信号传导，在骨骼成熟后成为糖尿病患者，提供了糖尿病骨病的临床前模型，但在解释糖尿病相关差异时，应考虑长期糖尿病期间的体重下降以及高血糖发作前的某些应变相关差异。
Individuals with type 2 diabetes (T2D) have a higher fracture risk compared to non-diabetics, even though their areal bone mineral density is normal to high. Identifying the mechanisms whereby diabetes lower fracture resistance requires well-characterized rodent models of diabetic bone disease. Toward that end, we hypothesized that the bone toughness, more so than bone strength, decreases with the duration of diabetes in ZDSD rats. Bones were harvested from male CD(SD) control rats and male ZDSD rats at 16-wks (before the onset of hyperglycemia), at 22-wks (5–6 wks of hyperglycemia), and at 29-wks (12–13 wks of hyperglycemia). There were at least 12 rats per strain per age group. At 16-wks, there was no difference in either body weight or glucose levels between the 2 rat groups. Within 2 weeks of switching all rats to a diet with 48% of kcal from fat, only the ZDSD rats developed hyperglycemia (>250 mg/dl). They also began to lose body weight at 21-wks. CD(SD) rats remained normoglycemic (<110 mg/dl) on the high fat diet and became obese (>600 g). From micro-computed tomography (µCT) analysis of a lumbar vertebra and distal femur, trabecular bone volume did not vary with age among the non-diabetic rats but was lower at 29-wks than at 16-wks or at 22-wks for the diabetic rats. Consistent with that finding, µCT-derived intra-cortical porosity (femur diaphysis) was higher for ZDSD following ~12 wks of hyperglycemia than for age-matched CD(SD) rats. Despite an age-related increase in mineralization in both rat strains (µCT and Raman spectroscopy), material strength of cortical bone (from three-point bending testing) increased with age only in the non-diabetic CD(SD) rats. Moreover, two other material properties, toughness (radius) and fracture toughness (femur), significantly decreased with the duration of T2D in ZDSD rats. This was accompanied by the increase in the levels of the pentosidine (femur). However, pentosidine was not significantly higher in diabetic than in non-diabetic bone at any time point. The ZDSD rat, which has normal leptin signaling and becomes diabetic after skeletal maturity, provides a pre-clinical model of diabetic bone disease, but a decrease in body weight during prolonged diabetes and certain strain-related differences before the onset of hyperglycemia should be taken into consideration when interpreting diabetes-related differences.