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

• 批准号: 10490260
• 负责人: KAREN C JOHNSON
• 金额: $ 60.97万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10490260
• 关键词: Biological; Blood specimen; Body Weight decreased; Bone Density; Cardiovascular Diseases; Cardiovascular system; Chemical Structure; Control Groups; Diabetes Mellitus; Disease; Dual-Energy X-Ray Absorptiometry; Education; Elderly; Etiology; Fasting; Fracture; Goals; Health; Health Expenditures; Hip Fractures; Hip region structure; Image; Incidence; Individual; Intervention; Lead; Link; Measurement; Measures; Mediating; Mediation; Mediator of activation protein; Methods; Molecular Target; Molecular Weight; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overweight; Participant; Patients; Pattern; Pelvis; Pharmaceutical Preparations; Plasma; Prevention strategy; Quality of life; Randomized; Randomized Clinical Trials; Risk; Scanning; Science; Serum; Shoulder Fractures; Subgroup; Trabecular Bone Score; Upper Extremity Fracture; Upper arm; Validation; Visit; Weight Gain; Weight maintenance regimen; base; biomarker discovery; blood glucose regulation; bone; bone health; bone imaging; bone loss; bone metabolism; bone preservation; bone quality; bone turnover; cardiovascular risk factor; comparison group; design; disability; follow-up; fracture risk; frailty; glycemic control; group intervention; improved; insight; lifestyle intervention; liquid chromatography mass spectrometry; metabolomics; mortality; novel; novel marker; obese patients; osteoporosis with pathological fracture; predictive marker; prevent; secondary outcome; skeletal; weight loss intervention

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.

减肥对于改善血糖的2型糖尿病（T2D）的超重或肥胖患者至关重要 控制，心血管危险因素和生活质量。但是，已经发现体重减轻是相关的 由于许多研究，包括糖尿病的健康作用，骨质流失和骨折风险增加（看 提前）试验，我们观察到体重减轻的强化生活方式干预（ILI）与 与糖尿病相比 T2D超重或肥胖患者中的支持和教育（DSE）（对照组）。虚弱的骨折是 毁灭性并代表骨质疏松骨折类型的一部分。我们还观察到ILI与 在未来的外观亚组中增加了骨质流失，后者还进行了双能X射线吸收法（DXA）扫描。 但是，连接ILI和骨折风险增加的机制仍然在很大程度上是未知的，但非常 对于开发有效保护骨骼和预防故意体重时断裂的有效方法很重要 损失。这项拟议的研究的总体目标是鉴定代谢组学变化，以介导ILI的效果 关于使用最先进的液相色谱法 - 质谱（LC-MS）基于代谢组学方法。在这项研究中，我们将包括4,659个展望 参与者（ILI中有2,357个，DSE为2,302），他们在基线和1年收集了血液样本 访问并进行了11。3年的中位随访，以造成骨折结果。其中有1,274名参与者（642 IN ILI和DSE中的632）在基线和第1年都进行了骨矿物质密度（BMD）的DXA扫描。 研究，我们将进一步测量血清骨转换标记（BTM）和重新分析DXA图像以获得 小梁骨评分（TBS）评估骨代谢和骨微体系结构（骨骼的指标 质量）在DXA子组中。一种全面的两阶段代谢组学方法，包括 非靶向/全局代谢组学分析，具有相对定量，然后进行化学结构验证 并且绝对量化将支持以下特定目的：目标1）检查ILI对 从基线到第1年的代谢组概况的变化；目的2）检查1年是否发生变化 代谢组谱与ILI对脆弱性骨折风险相关并介导。目标3） 检查代谢组谱的1年变化是否与BTMS，BMD和TBS的变化有关； 目标4）检查基线代谢组谱是否会改变ILI对脆弱裂缝风险的影响。 拟议的研究将提供有关增加的生物学机制的全面见解 ILI引起的脆弱骨折的风险。这些发现将有助于发现分子靶标的 故意减肥对骨骼健康的有害影响。该研究还将为 预测脆弱骨折的风险，并指导生活方式干预的个性化和优化 超重和肥胖患者T2D的体重减轻。