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

1型糖尿病(T1D)患者表现出脆性骨折的高风险，然而 对T1D的理解还不完全。面积骨密度(ABMD)的下降是有目共睹的，但 ABMD不足只解释了观察到的T1D骨折风险增加的20%。相反，骨骼的缺陷 微结构、周转和材料组成可能是高断裂风险的易感因素。在类型2中 糖尿病(T2D)，我们使用一种新的冲击显示骨材料强度指数(BMSi)降低 微压痕装置，我们发现，这也与皮肤反映的长期血糖有关 组织晚期糖基化终末产物(AGE)水平的自发荧光测量。尽管BMSI在 T2D，骨骼微结构被发现是完整的，如高分辨率外周定量评估 计算机断层扫描(HR-pQCT)。相比之下，在T1D中，主要缺陷存在于改变的微结构和 我们发现骨小梁厚度减少。然而，我们对T1D对骨小梁的影响知之甚少 形态、生物力学性能和骨材料强度。重要的是，T1D的发病通常是 在达到骨量峰值之前，几乎没有自然病史数据来说明骨量是如何增加的。 受到了影响。血糖控制和可变性是否可以预测骨缺陷也是未知的。为了 要了解T1D骨病的发病机制，我们必须了解T1D骨病的时间进程 T1D中的骨骼缺陷，具体地说，它们作为血糖控制的功能可能如何进展。一起， 这些观察结果强调了我们的中心假设：与T2D相比，T1D主要与 在骨量增加的高峰期，由于微结构的破坏而导致的骨强度降低，以及 这种干扰是由高血糖和血糖变异性引起的。因此，这一计划的总体目标是 应用：1)了解血糖控制与骨强度之间的关系 使用基于HR-pQCT的骨强度(包括骨小梁和皮质骨)估计T1D成人与对照组 成分和小梁形态)；2)阐明T1D的作用(包括血糖控制和 连续血糖监测的可变性)基于HR-pQCT的骨量峰值 对T1D儿童与对照组两年内骨强度的估计；3)检查两者之间的关系 长寿老人皮肤微压痕法测定骨材料强度与皮肤自发荧光法测定年龄的关系 站立的T1D成人与对照组。这项研究将提供有关T1D影响的全面数据 关于骨骼中有助于增强强度和抗骨折能力的元素。血糖控制对糖尿病患者的影响 横断面测量和前瞻性骨骼获取将决定骨骼脆性是否像其他 T1D的并发症与血糖控制不佳有关。这一结果应该有助于揭开 糖尿病骨骼脆性的发病机制，并成为后续研究制定策略的基础 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.