Skeletal Fragility in Type 1 Diabetes: Glycemic Control and Bone Strength

1型糖尿病（T1 D）患者显示脆性骨折的高风险，然而， T1 D还没有被完全理解。区域BMD（aBMD）的下降是公认的，但 aBMD不足仅解释了观察到的T1 D骨折风险增加的20%。相反， 微结构、周转和材料组成可能使骨折风险增高。2型 糖尿病（T2 D），我们已经表明降低骨材料强度指数（BMSi）使用一种新的影响， 微压痕装置，其中，我们发现，也与长期反射的皮肤 组织晚期糖基化终产物（AGE）水平的自体荧光测量。尽管BMSi降低， T2 D，通过高分辨率外周定量分析评估，发现骨骼微结构完整 计算机断层扫描（HR-pQCT）。相比之下，在T1 D中，原发性缺陷存在于改变的微结构中， 我们发现骨小梁厚度减少。然而，我们几乎没有关于T1 D对小梁细胞的影响的信息。 形态学、生物力学性能和骨材料强度。重要的是，T1 D的发作通常是 在达到峰值骨量之前，几乎没有自然史数据来证明骨增量是如何增加的。 受影响血糖控制和变异性是否能预测骨缺损也是未知的。为了 了解T1 D骨疾病的发病机制，因此，我们必须了解T1 D骨疾病的时间进程， T1 D中的骨骼缺陷，特别是它们如何作为血糖控制的函数而进展。在一起， 这些观察结果强调了我们的中心假设：与T2 D相反，T1 D主要与以下因素相关： 由于峰值骨量增加期间发生的微结构破坏导致骨强度下降，以及 这种破坏是由高血糖和血糖变异性引起的。因此，本项目的总体目标 应用：1）了解长期血糖控制与骨强度之间的关系， 使用基于HR-pQCT的骨强度估计值（包括骨小梁和骨皮质）比较T1 D成人与对照组 成分和小梁形态）; 2）阐明T1 D的作用（包括血糖控制和 动态葡萄糖监测的变异性）对骨量峰值增加的影响 T1 D儿童与对照组2年内骨强度的估计值; 3）检查T1 D儿童与对照组之间的关系 骨材料强度的微压痕和年龄积累的皮肤自发荧光在长- T1 D成人站立位与对照组。这项研究将提供有关T1 D影响的全面数据。 对骨骼中有助于增强强度和抗骨折性的元素的影响。血糖控制对 横截面测量和前瞻性骨采集将确定骨骼脆性是否像其他 T1 D的并发症与血糖控制不良有关。这些结果应该有助于解开 糖尿病骨骼脆弱性的发病机制，并成为后续研究的基础，以制定战略 以减轻并理想地防止这一脆弱人群的骨折。

Patients with type 1 diabetes (T1D) display a high risk of fragility fractures, yet the skeletal pathophysiology of T1D is incompletely understood. Decreases in areal BMD (aBMD) are well-established, but the magnitude of the aBMD deficit explains only 20% of the observed increase in T1D fracture risk. Rather, deficits in bone microarchitecture, turnover and material composition likely predispose to the high fracture risk. In type 2 diabetes (T2D), we have shown reduced bone material strength index (BMSi) using a novel impact microindentation device, which, we found, also correlated with long-term glycemia as reflected by a skin autofluorescence measure of tissue advanced glycation endproduct (AGE) levels. Despite reduced BMSi in T2D, skeletal microarchitecture was found to be intact, as assessed by high resolution peripheral quantitative computed tomography (HR-pQCT). In contrast, in T1D, primary deficits reside in altered microarchitecture and we find reduced trabecular thickness. However, we have little information on effects of T1D on trabecular morphology, biomechanical properties and bone material strength. Importantly, the onset of T1D is generally before attainment of peak bone mass, yet there is little natural history data to demonstrate how bone accrual is impacted. It is also unknown whether glycemic control and variability predict bone deficits. In order to understand the pathogenesis of T1D bone disease, it is thus imperative that we understand the time course of skeletal deficits in T1D, and specifically, how they might progress as a function of glycemic control. Together, these observations underscore our central hypothesis: T1D, in contrast to T2D, is primarily associated with decrements in bone strength due to disrupted microarchitecture occurring during peak bone mass accrual, and that this disruption arises from hyperglycemia and glycemic variability. Thus, the overall goals of this application are: 1) to understand the relationship between glycemic control and bone strength in long-standing T1D adults versus controls using HR-pQCT-based estimates of bone strength (including trabecular and cortical components and trabecular morphology); 2) to elucidate the effects of T1D (including glycemic control and variability by continuous glucose monitoring) on the peak accrual of bone mass by following HR-pQCT-based estimates of bone strength over 2 years in T1D children versus controls; and 3) to examine the relationship between bone material strength by microindentation and AGE accumulation by skin autofluorescence in long- standing T1D adults versus controls. The research will provide comprehensive data about the effects of T1D on the elements of bone that contribute to strength and fracture resistance. The effects of glycemic control on cross-sectional measures and prospective bone acquisition will determine whether skeletal fragility, like other complications of T1D, is associated with poor glycemic control. The results should help unravel the pathogenesis of diabetic skeletal fragility and become a foundation for follow-up studies to develop strategies to mitigate and ideally prevent fractures in this vulnerable population.