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，人们发现体重减轻与 许多研究表明，骨质流失和骨折风险增加，包括糖尿病健康行动（看 AHEAD）试验中，我们观察到用于减肥的强化生活方式干预（ILI）与 与糖尿病相比，衰弱性骨折（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）。衰弱性骨折是 破坏性的，代表骨质疏松性骨折类型的一部分。我们还观察到 ILI 与 在进行双能 X 射线吸收测定 (DXA) 扫描的 Look AHEAD 亚组中，骨质流失增加。 然而，ILI 与骨折风险增加之间的联系机制仍然很大程度上未知，但非常重要。 对于开发有效的方法来保护骨骼和防止有意负重期间骨折非常重要 损失。这项研究的总体目标是确定介导 ILI 影响的代谢组学变化 在使用最先进的液相色谱的 Look AHEAD 试验中，研究了脆性骨折的风险增加 - 基于质谱 (LC-MS) 的代谢组学方法。在本研究中，我们将包括 4,659 个 Look AHEAD 参与者（ILI 中 2,357 名，DSE 中 2,302 名）在基线和 1 年期间采集了血液样本 访视并对骨折结果进行了 11.3 年的中位随访。其中，1,274 名参与者（642 名 ILI 和 DSE 中的 632）还在基线和第一年进行了骨矿物质密度 (BMD) 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），用于评估骨代谢和骨微结构（骨的指标） 质量）在 DXA 子组中。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，进行相对定量，然后进行化学结构验证 和绝对定量，将支持以下具体目标： 目标 1) 检查 ILI 对 从基线到第一年代谢组学特征的变化；目标 2) 检查一年内是否发生变化 代谢组学特征与 ILI 对脆性骨折风险的影响相关并介导其影响；目标 3) 至 检查代谢组学特征的 1 年变化是否与 BTM、BMD 和 TBS 的变化相关； 目标 4) 检查基线代谢组学特征是否改变 ILI 对脆性骨折风险的影响。 拟议的研究将提供对增加的生物学机制的全面见解。 ILI 导致脆性骨折的风险。这些发现将有助于发现阻断该疾病的分子靶点 有意减肥对骨骼健康的不利影响。该研究还将提供新的生物标志物 预测脆性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 T2D 患者体重减轻。