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

• 批准号: 10684140
• 负责人: ANN V SCHWARTZ
• 金额: $ 66.92万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10684140
• 关键词: Adult; Affect; Age; Aging; Albuminuria; Allopurinol; Ancillary Study; Archives; Biological Availability; Biological Markers; Biopsy; Bone Density; Bone Diseases; Chronic Kidney Failure; Cohort Studies; Complement; Complication; Complications of Diabetes Mellitus; Continuous Glucose Monitor; Data; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathy; Dual-Energy X-Ray Absorptiometry; Epidemiology; Fracture; Functional disorder; Geometry; Glomerular Filtration Rate; Glucose; Glycosylated hemoglobin A; 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; Structure; 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; glycemic control; human old age (65+); men; mortality; negative affect; participant enrollment; post intervention; prevent; screening; screening guidelines; skeletal

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.

项目摘要/摘要 1型糖尿病(T1D)与一生中骨折风险的增加有关。AS 患有T1D的人现在活到了高龄，当骨折的发病率和死亡率最高时，这是至关重要的 了解这种骨骼的脆性，并确定降低骨折风险的策略。骨密度为 减少，但骨折抬高与这种减少不成比例，表明其他因素--“骨” 质量“--也是骨骼脆弱的原因之一。这些症状可能包括骨转换率低和骨质受损。 几何结构和微观结构。糖尿病微血管并发症的存在与 特别是骨骼的脆性，但到目前为止的研究还无法解开每一个人的具体贡献 并发症，也不能确定相关性是否独立于血糖控制。对微血管的影响 并发症，糖尿病肾病可能尤其有害，因为T1D的其他骨骼影响可能是 慢性肾脏疾病的骨骼和矿物质紊乱，包括异常的骨转换 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T1D骨骼，在糖尿病骨骼脆性的病理生理学中起着关键作用。 Perl试验提供了一个独特的机会来了解这些影响的重叠影响，因为 它广泛地表征了患有T1D和糖尿病肾病的成年参与者的肾功能 严重程度各不相同。这项为期3年的别嘌醇与安慰剂对肾功能影响的试验已经结束， 参与者参加了一项观察性的试验后队列研究。在7个Perl中心的148名参与者中， 我们提出了一项辅助研究，将增加骨密度的骨骼成像(使用双能X射线 骨密度仪)和骨骼微结构和估计强度(使用高分辨率外周定量 计算机断层扫描)。我们还将增加对存储的三个时间点的血清样本的分析 Perl.一组参与者(N=25)将接受四环素标记的骨活检。我们会估计 金标碘海醇GFR和纵向测量的蛋白尿与骨骼的关系 参数(目标1a)。然后，我们将确定这些关系是否会在更广泛的肾脏范围内发生变化 功能，通过将来自Perl的数据与持续获取的220名成年人的骨骼成像数据相结合 EDIC研究，其中许多人肾小球滤过率正常，没有蛋白尿(目标1b)。接下来我们将确定血糖是否会升高 控制与Perl中的骨架参数独立关联(目标2)。最后，我们将检查是否 甲状旁腺激素和骨转换标志物水平的高低与骨骼参数有关 维生素D代谢产物的改变是否部分解释了肾脏与骨骼的关系(目标3)。在活组织检查中 子集，我们将探索甲状旁腺激素和骨转换标志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和 干预措施。最终，它可以帮助降低我们老龄化的T1D人群的骨折风险。