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.

体重减轻对于超重或肥胖的2型糖尿病（T2D）患者改善血糖至关重要