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Intensive Lifestyle Intervention, Metabolomics, and Risk of Frailty Fracture in Overweight or Obese Patients with Type 2 Diabetes

超重或肥胖 2 型糖尿病患者的强化生活方式干预、代谢组学和衰弱性骨折风险

基本信息

批准号：
10661065
负责人：
KAREN C JOHNSON
金额：
$ 61.67万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-05-31
项目状态：
未结题

项目摘要

Weight loss is critical to overweight or obese patients with type 2 diabetes (T2D) for improving glycemic control, cardiovascular risk factors, and quality of life. However, weight loss has been found to be associated with increased bone loss and risk for fractures by many studies, including the Action for Health in Diabetes (Look AHEAD) trial in which we observed an intensive lifestyle intervention (ILI) for weight loss was associated with 39% increased risk for frailty fracture (hip, pelvis, upper arm, or shoulder fractures) compared with diabetes support and education (DSE) (control group) among overweight or obese patients with T2D. Frailty fractures are devastating and represent a part of osteoporotic fracture types. We also observed the ILI was associated with increased bone loss in a subgroup of Look AHEAD who also had dual-energy X-ray absorptiometry (DXA) scans. However, the mechanisms linking the ILI and increased risk of fracture are still largely unknown but very important for developing effective methods for protecting bone and preventing fracture during intentional weight loss. The overall goal of this proposed study is to identify metabolomic changes which mediate the effect of ILI on the increased risk for frailty fracture in the Look AHEAD trial using a state-of-the-art liquid chromatography- mass spectrometry (LC-MS)-based metabolomics approach. In this study, we will include 4,659 Look AHEAD participants (2,357 in ILI and 2,302 in DSE) who had blood samples collected at both baseline and the 1-year visit and had a median follow-up of 11.3 years for fracture outcomes. Among those, 1,274 participants (642 in ILI and 632 in DSE) also had DXA scans for bone mineral density (BMD) at both baseline and year 1. In this study, we will further measure serum bone turnover markers (BTMs) and reanalyze DXA images to obtain the trabecular bone score (TBS) to evaluate bone metabolism and bone microarchitecture (an indicator of bone quality) in the DXA subgroup. A comprehensive two-stage metabolomics approach, including an untargeted/global metabolomics analysis with relative quantification followed by chemical structure validation and absolute quantification, will support the following Specific Aims: Aim 1) To examine the effects of ILI on changes in metabolomic profiles from baseline to year 1; Aim 2) To examine whether 1-year changes in metabolomic profiles are associated with and mediate the effect of ILI on the risk of frailty fracture; Aim 3) To examine whether 1-year changes in metabolomic profiles are associated with changes in BTMs, BMD, and TBS; and Aim 4) To examine whether baseline metabolomic profiles modify the effect of ILI on the risk of frailty fracture. The proposed study will provide comprehensive insights into the biological mechanisms underlying the increased risk of frailty fracture caused by the ILI. These findings will help discover molecular targets for blocking the detrimental effect of intentional weight loss on bone health. The study will also provide novel biomarkers for predicting the risk of frailty fracture and directing the personalization and optimization of lifestyle intervention for weight loss among overweight and obese patients with T2D.

减肥对于超重或肥胖的2型糖尿病(T2D)患者改善血糖至关重要控制、心血管危险因素和生活质量。然而，研究发现，体重减轻与骨丢失和骨折风险增加的许多研究，包括糖尿病健康行动(查看在我们观察到强化生活方式干预(ILI)减肥的试验中，与糖尿病相比，脆弱骨折(髋部、骨盆、上臂或肩部骨折)的风险增加39% 超重或肥胖T2D患者的支持和教育(DSE)(对照组)。脆弱的骨折是破坏性骨折，是骨质疏松性骨折的一部分。我们还观察到ILI与同时接受双能X线骨密度仪(DXA)扫描的前瞻小组中，骨丢失增加。然而，ILI与骨折风险增加之间的联系机制在很大程度上仍不清楚，但非常在意定重量中开发有效的护骨和预防骨折方法的重要意义损失。这项拟议研究的总体目标是确定调节ILI效果的代谢变化在前瞻试验中使用最先进的液相色谱仪增加脆性骨折的风险基于LC-MS的代谢组学方法。在这项研究中，我们将包括4659个展望未来在基线和一年内都采集了血样的参与者(ILI组2357人，DSE组2302人) 随访时间中位数为11.3年。其中，1,274名参与者(642名 Ili和DSE中的632)也在基线和第一年进行了骨密度(BMD)的DXA扫描。研究中，我们将进一步测量血清骨转换标志物(BTM)并重新分析DXA图像以获得骨小梁评分(TBS)用于评价骨代谢和骨微结构(骨指标质量)在DXA亚组。一种全面的两阶段代谢组学方法，包括相对定量后化学结构验证的非靶向/全球代谢组学分析和绝对量化，将支持以下具体目标：目的1)检查ILI对从基线到第1年的代谢组变化；目标2)检查1年的变化是否代谢组学与ILI对脆性骨折风险的影响有关并起中介作用；目标3) 检查代谢组谱的1年变化是否与BTMS、BMD和TBS的变化相关；目的4)检验基线代谢谱是否改变ILI对脆性骨折风险的影响。这项拟议的研究将提供对导致增加的生物机制的全面见解。 ILI导致的脆性骨折的风险。这些发现将有助于发现阻断细胞外信号通路的分子靶点。故意减肥对骨骼健康的不利影响。这项研究还将提供新的生物标志物预测脆性骨折的风险，指导个性化和最优化的生活方式干预 T2D超重和肥胖患者的体重减轻。