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

1 型糖尿病的骨骼健康和糖尿病肾病的作用

基本信息

批准号：
10459481
负责人：
ANN V SCHWARTZ
金额：
$ 66.62万
依托单位：
NORTHERN CALIFORNIA INSTITUTE/RES/EDU
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10459481
关键词：
Adult Affect Age Aging Albuminuria Allopurinol Ancillary Study Archives Biological Markers Biopsy Bone Density Bone Diseases Chronic Kidney Failure Cohort Studies Complement Complication Complications of Diabetes Mellitus Data Diabetes Mellitus Diabetic Angiopathies Diabetic Nephropathy Dual-Energy X-Ray Absorptiometry Enrollment Epidemiology Fracture Functional disorder Geometry Glomerular Filtration Rate Glucose Glycosylated hemoglobin A Gold Health Hip Fractures Hormones Hyperglycemia Image Impairment Individual Insulin-Dependent Diabetes Mellitus Intervention Iohexol Kidney Kidney Diseases Label Longevity Measurement Measures Metabolism Microvascular Dysfunction Minerals Morbidity - disease rate PTH gene Participant Patient Care Pattern Peripheral Persons Placebos Play Population Prevention Randomized Recording of previous events Renal function Research Resolution Risk Risk Factors Role Serum Severities Shapes Skeleton Specimen Tetracyclines Time Uric Acid Visit Vitamin D Vitamin D-Binding Protein Woman X-Ray Computed Tomography bone bone fragility bone geometry bone imaging bone mass bone quality bone strength bone turnover clinical care diabetic epidemiologic data evidence based guidelines fracture risk glucose monitor glycemic control men mortality negative affect post intervention prevent protein metabolite screening screening guidelines skeletal

项目摘要

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.

项目概要/摘要 1 型糖尿病 (T1D) 与一生中骨折风险增加相关。 T1D 患者现在可以活到老年，此时骨折的发病率和死亡率最高，因此至关重要了解这种骨骼脆弱性并确定降低骨矿物质密度的策略。减少，但骨折的升高与这种减少不成比例，这表明其他因素——“骨质量”——也会导致骨骼脆弱，其中可能包括骨转换率低和骨骼受损。几何形状和微观结构。糖尿病微血管并发症的存在与相关。特别是骨骼脆弱性，但迄今为止的研究还无法理清每种骨骼的具体贡献并发症，也无法确定相关性是否独立于血糖控制。并发症，糖尿病肾病可能尤其令人痛苦，因为 T1D 的其他骨骼影响可能是因慢性肾病引起的骨骼和矿物质紊乱（包括骨转换异常）而加剧我们的中心假设是糖尿病肾病尤其影响 T1D 骨骼已经很脆弱，并且在糖尿病骨骼脆弱的病理生理学中发挥着关键作用。 PERL 试验提供了一个独特的机会来了解这些效应的重叠影响，因为它主要表征了患有 T1D 和糖尿病肾病的成年参与者的肾功能这项为期 3 年的别嘌呤醇与安慰剂对肾功能影响的试验已经结束，并且参与者参加了一项观察性试验后队列研究，共有 7 个 PERL 中心的 148 名参与者参加。我们提出一项辅助研究，增加骨密度骨骼成像（使用双能 X 射线吸收测定法）和骨微观结构和估计强度（具有高分辨率外周定量计算机断层扫描）我们还将添加对期间 3 个时间点存储的血清样本的分析。 PERL。我们将估计一部分参与者（N = 25）将接受四环素标记的骨活检。金标准碘海醇 GFR 和白蛋白尿（纵向测量）与骨骼肌的关系然后，我们将确定这些关系在更广泛的肾脏中是否有所不同。通过将 PERL 的数据与来自 220 名成人的一致采集的骨骼成像数据相结合， EDIC 研究，其中许多人的 GFR 正常且无蛋白尿（目标 1b），接下来我们将确定血糖是否正常。控制与 PERL 中的骨架参数独立相关（目标 2）。高或低甲状旁腺激素和骨转换标志物水平与骨骼参数相关，并且维生素 D 代谢的改变是否可以部分解释肾与骨的关系（目标 3）。子集，我们将探讨 PTH 和骨转换是否将标记物与组织形态学转换相关。这项研究有可能通过告知筛查方法和方法来塑造 T1D 患者的护理最终，它可以帮助降低老龄化 T1D 人群的骨折风险。