Skeletal Health in Type 1 Diabetes and the Role of Diabetic Kidney Disease

项目总结/摘要 1型糖尿病（T1 D）与整个生命周期中骨折风险增加有关。作为 患有T1 D的个体现在可以活到老年，此时骨折的发病率和死亡率最高， 了解这种骨骼脆弱性，并确定降低骨折风险的策略。骨密度 减少，但骨折是升高不成比例，这种减少，表明其他因素-“骨 质量”-也有助于骨骼的脆弱性。这些可能包括低骨转换和受损的骨 几何形状和微观结构。糖尿病微血管并发症的存在与 特别是骨骼脆弱性，但迄今为止的研究一直无法解开每一个具体的贡献 并发症，也不确定是否关联独立于血糖控制。微血管 并发症，糖尿病肾病可能是特别有害的，因为T1 D的其他骨骼影响可能是 伴有慢性肾病的骨和矿物质紊乱，包括骨转换异常 和维生素D代谢。我们的中心假设是糖尿病肾病特别影响 已经脆弱的T1 D骨骼，并在糖尿病骨骼脆弱性的病理生理学中起关键作用。 PERL试验为了解这些效应的重叠影响提供了一个独特的机会， 它广泛地描述了患有T1 D和糖尿病肾病的成年参与者的肾功能， 不同的严重程度。这项为期3年的别嘌呤醇与安慰剂对肾功能影响的试验已经结束， 参与者被纳入观察性试验后队列研究。在7个PERL中心的148名参与者中， 我们建议进行一项辅助研究，增加骨密度的骨骼成像（使用双能X射线 骨吸收测定法）和骨显微结构和估计强度（高分辨率外周定量 计算机断层扫描）。我们还将增加对3个时间点储存的血清标本的分析， 佩尔。一部分受试者（N=25）将接受四环素标记的骨活检。我们估计 经尿道测量的金标准碘海醇GFR和白蛋白尿与骨骼 参数（目标1a）。然后，我们将确定这些关系是否在更广泛的肾脏疾病中有所不同。 功能，通过将PERL的数据与来自220名成年人的一致获得的骨骼成像数据相结合， EDIC研究，其中许多人GFR正常，无蛋白尿（Aim 1b）。我们接下来将确定血糖 控件独立地与PERL中的骨架参数相关联（Aim 2）。最后，我们将研究是否 甲状旁腺激素和骨转换标志物水平的高低与骨骼参数相关， 维生素D代谢物的改变是否部分解释了肾骨关系（目的3）。在活组织检查中 我们将探讨PTH和骨转换标志物是否与组织形态计量学转换相关。 这项研究有可能通过告知筛查方法来塑造T1 D患者的护理， 干预措施。最终，它可以帮助降低我们老龄化T1 D人群的骨折风险。

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is associated with increased risk of fracture throughout the lifespan. As individuals with T1D now live to older ages, when morbidity and mortality from fracture are greatest, it is crucial to understand this skeletal fragility and identify strategies to mitigate fracture risk. Bone mineral density is reduced, but fracture is elevated out of proportion to this reduction, indicating that other factors—“bone quality”—also contribute to the skeletal fragility. These may include low bone turnover and compromised bone geometry and microstructure. The presence of a diabetes microvascular complication is associated with particular skeletal fragility, but studies to date have been unable to disentangle specific contributions of each complication, nor to determine whether associations are independent of glycemic control. Of the microvascular complications, diabetic kidney disease may be especially detrimental, as other skeletal effects of T1D may be compounded by bone and mineral derangements of chronic kidney disease, including abnormal bone turnover and vitamin D metabolism. Our central hypothesis is that diabetic kidney disease particularly affects the already vulnerable T1D skeleton and plays a key role in the pathophysiology of diabetic skeletal fragility. The PERL trial presents a unique opportunity to understand the overlapping impact of these effects, as it has extensively characterized the kidney function of adult participants with T1D and diabetic kidney disease of varied severity. This 3-year trial of the effects of allopurinol vs. placebo on kidney function has ended, and participants are enrolled in an observational post-trial cohort study. In the 148 participants at 7 PERL centers, we propose an ancillary study that will add skeletal imaging for bone density (with dual-energy X-ray absorptiometry) and bone microstructure and estimated strength (with high-resolution peripheral quantitative computed tomography). We will also add analyses on stored serum specimens from 3 time points during PERL. A subset of participants (N=25) will undergo tetracycline-labeled bone biopsy. We will estimate relationships of gold-standard iohexol GFR and albuminuria—measured longitudinally—with skeletal parameters (Aim 1a). Then, we will determine if those relationships vary across a wider spectrum of kidney function, by combining data from PERL with consistently-acquired skeletal imaging data from 220 adults in the EDIC study, many of whom have normal GFR and no albuminuria (Aim 1b). We will next determine if glycemic control is independently associated with skeletal parameters in PERL (Aim 2). Finally, we will examine whether high or low parathyroid hormone and bone turnover marker levels are associated with skeletal parameters, and whether altered vitamin D metabolites partially explain the kidney-bone relationship (Aim 3). In the biopsy subset, we will explore whether PTH and bone turnover markers correlate with histomorphometric turnover. This research has the potential to shape the care of patients with T1D by informing screening approaches and interventions. Ultimately, it could help reduce fracture risk in our aging T1D population.