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

体重减轻对于超重或肥胖的2型糖尿病（T2 D）患者至关重要， 控制，心血管危险因素和生活质量。然而，减肥被发现与 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（Look AHEAD）试验中，我们观察到强化生活方式干预（ILI）与体重减轻相关， 与糖尿病相比，脆弱性骨折（髋部、骨盆、上臂或肩部骨折）的风险增加39% 支持和教育（DSE）（对照组）超重或肥胖T2 D患者。脆弱性骨折是 破坏性很强，代表了一部分非破坏性骨折类型。我们还观察到ILI与 Look AHEAD的一个亚组也进行了双能X线骨密度仪（DXA）扫描，骨丢失增加。 然而，ILI和骨折风险增加之间的联系机制在很大程度上仍然未知， 对于开发在有意负重期间保护骨骼和预防骨折的有效方法具有重要意义 损失本研究的总体目标是确定介导ILI效应的代谢组学变化 在Look AHEAD试验中使用最先进的液相色谱法， 质谱（LC-MS）为基础的代谢组学方法。在这项研究中，我们将包括4，659个展望未来， 参与者（ILI组2，357人，DSE组2，302人）在基线和1年时采集了血液样本 随访，骨折结局的中位随访时间为11.3年。其中，1，274名参与者（642人在 ILI和DSE中的632例）在基线和第1年也进行了DXA骨矿物质密度（BMD）扫描。在这 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），以评估骨代谢和骨微结构（骨代谢的指标） DXA亚组中的质量）。一个全面的两阶段代谢组学方法，包括 非靶向/整体代谢组学分析，相对定量，随后进行化学结构验证 和绝对定量，将支持以下具体目的：目的1）检查ILI对 从基线到第1年代谢组学特征的变化;目的2）检查代谢组学特征的1年变化是否 代谢组学特征与ILI对脆弱性骨折风险的影响相关，并介导ILI对脆弱性骨折风险的影响;目的3） 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; 和目的4）检查基线代谢组学谱是否改变ILI对脆弱性骨折风险的影响。 这项拟议的研究将提供全面的见解，以了解增加的生物学机制。 ILI导致的脆弱性骨折风险。这些发现将有助于发现分子靶点， 故意减肥对骨骼健康的有害影响。该研究还将提供新的生物标志物， 预测脆弱性骨折的风险，指导个性化和优化生活方式干预， 超重和肥胖T2 D患者的体重减轻。

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.