Delineating mechanisms of skeletal fragility in older adults with Type 1 Diabetes

项目摘要 当前提案是对最近资助的R 01 DK 124710的竞争性修订，将扩大范围 以及家长补助金的潜在影响1型糖尿病（T1 D）的常见并发症 并且在老年人中尤其令人担忧。然而，骨骼脆弱性的潜在机制并不清楚， 明白虽然血管缺陷是众所周知的糖尿病并发症，但其对骨血流的影响 监管尚未探索。因此，本建议旨在研究糖尿病诱导的 血管缺陷对骨循环和骨骼脆弱性的队列中的老年人的父母补助金。 使用一种新的方法，近红外光谱（NIRS），我们将非侵入性地评估胫骨血流， 人类和每时每刻的基础上。采用近红外光谱，目标1将调查老年人是否与 与对照组相比，T1 D组胫骨血管的肌源性血管舒张较小，肌源性血管收缩较大。 非糖尿病对照组。目的2将探讨老年T1 D患者是否具有钝化的一氧化氮（NO）介导的 与非糖尿病对照组相比，胫骨血管系统的血管舒张。此外，目标3将探讨 胫骨血管反应（肌源性血管舒张、肌源性血管收缩、NO介导的 血管舒张）与微血管疾病负担、外周血管钙化和血糖控制之间的关系。 患有T1 D的成年人。最后，目标4将研究胫骨血管反应与胫骨 T1 D老年人的微结构。我们组建了一支高度跨学科的团队， 补充专业知识，以执行这项研究，我们将利用现有的研究队列的父母补助金 以高度成本效益的方式提供;本提案将利用父母补助金的若干摊款 并且患者负担将是最小的，需要单次研究访问。这项研究将首次提供 在T1 D成人体内骨血流调节的表征，并将增加宝贵的见解 血管并发症如何损害老年T1 D患者的骨结构和强度。 该项目的成功完成将为未来研究新的治疗方法奠定基础。 老年糖尿病患者的骨骼健康。

PROJECT SUMMARY The current proposal is a competitive revision for the recently funded R01DK124710 that will expand the scope and potential impact of the parent grant. Skeletal fragility is a recognized complication of Type 1 diabetes (T1D) and is of particular concern among older adults. However, the mechanisms underlying skeletal fragility are poorly understood. While vascular deficits are a well-known complication of diabetes, their effect on bone blood flow regulation has not been explored. Thus, this proposal seeks to investigate the contribution of diabetes-induced vascular deficits on bone circulation and skeletal fragility within the cohort of older adults of the parent grant. Using a novel approach, near infrared spectroscopy (NIRS), we will non-invasively assess tibial blood flow in humans and on a moment-by-moment basis. Employing NIRS, Aim 1 will investigate whether older adults with T1D have lesser myogenic vasodilation and greater myogenic vasoconstriction in the tibial vasculature compared to nondiabetic controls. Aim 2 will explore whether older adults with T1D have blunted nitric oxide (NO)-mediated vasodilation in the tibial vasculature compared to nondiabetic controls. Furthermore, Aim 3 will explore the relationship of tibial vascular responses (myogenic vasodilation, myogenic vasoconstriction, NO-mediated vasodilation) to microvascular disease burden, peripheral vascular calcification, and glycemic control in older adults with T1D. Lastly, Aim 4 will investigate the relationship between tibial vascular responses and tibial microarchitecture among older adults with T1D. We have assembled a highly interdisciplinary team with complementary expertise to perform this study and we will leverage the existing study cohort of the parent grant in a highly cost-efficient manner; several assessments of the parent grant will be utilized in the current proposal and the patient burden will be minimal, requiring a single study visit. The proposed research will provide the first ever characterization of in vivo bone blood flow regulation among adults with T1D and will add invaluable insight into how vascular complications may compromise bone structure and strength in older adults with T1D. Successful completion of this project will provide the foundation for future work towards novel treatments for bone health in older adults with diabetes.