Bone marrow fat and skeletal health in type 2 diabetes

2 型糖尿病患者的骨髓脂肪和骨骼健康

• 批准号: 9891879
• 负责人: Tiffany Youngun Kim
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9891879
• 关键词: Address; Adipocytes; Affect; Antidiabetic Drugs; Behavior; Biometry; Bone Density; Bone Diseases; Bone Marrow; Caring; Cell Count; Clinical Investigator; Clinical Research; Complication; Complications of Diabetes Mellitus; Data; Death Rate; Diabetes Mellitus; Differentiated Gene; Dual-Energy X-Ray Absorptiometry; Enrollment; Epidemiology; Fatty acid glycerol esters; Flow Cytometry; Fracture; Fracture Healing; Funding; Future; Gastric Bypass; Gene Expression; Glycosylated hemoglobin A; Goals; Health; Healthcare; Hip Fractures; Impairment; Individual; Investigation; K-Series Research Career Programs; Lead; Link; Magnetic Resonance Spectroscopy; Marrow; Measures; Medical; Medical Care Costs; Mentors; Mentorship; Mesenchymal Stem Cells; Metabolic; Metabolism; Methods; Non-Insulin-Dependent Diabetes Mellitus; Organ; Osteoblasts; Osteogenesis; Osteoporosis; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Peripheral; Peripheral Blood Mononuclear Cell; Physicians; Play; Porosity; Positioning Attribute; Postoperative Complications; Postoperative Period; Prevalence; Preventive; Prospective Studies; Prospective cohort study; Radial; Radiology Specialty; Reporting; Research; Research Design; Research Personnel; Research Training; Resolution; Role; Serum; Shapes; Site; Skeleton; Therapeutic; Trabecular Bone Score; Training; Unsaturated Fats; Veterans; X-Ray Computed Tomography; adult obesity; bariatric surgery; bone; bone health; bone imaging; bone mass; bone quality; bone turnover; design; diabetic bone disease; economic cost; effective therapy; experience; falls; fracture risk; glycemic control; health administration; high risk; imaging modality; improved; insight; laboratory experience; lipid biosynthesis; lipid metabolism; mortality risk; negative affect; novel; osteoblast differentiation; preservation; progenitor; programs; skeletal; skills; spine bone structure; stem cells; tibia

Dr. Kim’s long-term goal is to be a VA physician investigator, elucidating mechanisms of diabetic bone disease in order to reduce fracture risk in people with diabetes. There is growing recognition that bone disease is a complication of type 2 diabetes mellitus (T2DM). In T2DM, hip fracture risk is increased by more than a third, and after fracture, individuals with T2DM have higher rates of postoperative complications and a higher risk of mortality. Fracture risk is elevated even after controlling for falls, and hip fractures occur despite preserved or higher bone mineral density (BMD). The fat within the bone marrow is proposed to play a pathogenic role in diabetic bone disease, as fat and bone are intimately related within the marrow microenvironment. Adipocytes and osteoblasts share a common mesenchymal stem cell precursor, and adipogenesis could occur at the expense of osteoblastogenesis. Indeed, greater levels of marrow fat content are associated with lower BMD and higher fracture risk. However, it is unknown whether marrow fat can be manipulated to improve diabetic bone disease. Hemoglobin A1c (HbA1c) positively correlates with higher levels of marrow fat, so enhanced glycemic control might normalize marrow fat and improve bone outcomes. Given the widespread prevalence of diabetes and the medical and economic costs of fractures, there is an urgent need to understand diabetic bone disease to identify targeted preventive and therapeutic strategies. During the Career Development Award-2 (CDA-2) period, Dr. Kim’s goal is to acquire the training and implement the studies needed to understand the effects of improved glycemic control on marrow fat and bone health. She will gain expertise in valuable clinical research and translational methods that will position her to become a leader in the field of diabetic bone disease. Dr. Kim will enroll and follow 75 Veterans with poorly controlled T2DM (HbA1c 8.5-12.0%) who are working with their clinicians to improve glycemic control. She will determine the effects of improved glycemic control on bone marrow fat (Aim 1) and the relationship between changes in marrow fat with bone quality and mass (Aim 2). Pursuit of these aims will involve critical training in the design and implementation of a prospective cohort study. Dr. Kim will use advanced and sensitive imaging modalities (including magnetic resonance spectroscopy, high-resolution peripheral quantitative computed tomography) to assess marrow fat and bone outcomes at baseline and then after 1 year of intensified medical management. Dr. Kim will also use cutting edge translational methods to explore the role of osteoblast differentiation as a pathway linking marrow fat and bone outcomes (Aim 3). This will include characterizing circulating osteoblast progenitor cells by flow cytometry and evaluating expression of osteoblast differentiation genes. Training in advanced diabetes and lipid metabolism will allow Dr. Kim to interpret these findings and gain important insights into the pathogenesis of diabetic bone disease. This research is expected to advance understanding of marrow fat behavior, which may lead to targeted preventive and therapeutic strategies for diabetic bone disease and osteoporosis. Dr. Kim has assembled a diverse mentorship team comprised of experts in osteoporosis, metabolism, epidemiology, biostatistics, and radiology. Her training will involve a combination of individual tutorials with her mentors and scientific advisors, hands-on experience, and formal coursework. The proposed research will provide Dr. Kim with preliminary data for a larger and longer-term prospective study of diabetic bone disease, which she will propose in a Merit Review application submitted before the end of the CDA-2 period. Dr. Kim is committed to improving the health care of Veterans through clinical research, and with her proposed research and training, she will develop a thriving research program at the VA.

金博士的长期目标是成为一名退伍军人事务部医生调查员，阐明糖尿病骨的机制。 为了降低糖尿病患者的骨折风险，人们越来越认识到， 是2型糖尿病（T2 DM）的并发症。在T2 DM中，髋部骨折的风险增加超过 第三，骨折后，T2 DM患者的术后并发症发生率较高， 死亡风险。即使在控制了福尔斯跌倒后，骨折的风险也会升高， 保持或更高的骨矿物质密度（BMD）。骨髓中的脂肪被认为是 糖尿病骨病的致病作用，因为脂肪和骨骼在骨髓中密切相关 微环境脂肪细胞和成骨细胞具有共同的间充质干细胞前体， 脂肪形成可能以成骨细胞形成为代价而发生。事实上，更高水平的骨髓脂肪含量 与较低的BMD和较高的骨折风险相关。然而，骨髓脂肪是否可以 用来改善糖尿病性骨病血红蛋白A1 c（HbA 1c）与较高的 因此，加强血糖控制可能会使骨髓脂肪正常化并改善骨骼结果。 考虑到糖尿病的广泛流行以及骨折的医疗和经济成本， 迫切需要了解糖尿病性骨病，以确定有针对性的预防和治疗策略。 在职业发展奖-2（CDA-2）期间，金博士的目标是获得培训， 开展研究，了解改善血糖控制对骨髓脂肪和骨骼的影响 健康她将获得宝贵的临床研究和转化方法的专业知识，这将使她能够 成为糖尿病骨病领域的领导者。金博士将招募并跟踪75名退伍军人， 受控制的T2 DM（HbA 1c 8.5-12.0%），他们正在与临床医生合作改善血糖控制。她将 确定改善血糖控制对骨髓脂肪的影响（目标1）以及 骨髓脂肪与骨质量和骨质量的变化（目的2）。追求这些目标将涉及以下方面的关键培训： 前瞻性队列研究的设计和实施。金博士将使用先进而灵敏的成像技术 模态（包括磁共振波谱、高分辨率外周定量计算 断层扫描），以评估基线时的骨髓脂肪和骨结局，然后在1年强化医疗后 管理金博士还将使用尖端的翻译方法来探索成骨细胞的作用， 分化作为连接骨髓脂肪和骨结果的途径（Aim 3）。这将包括表征 流式细胞术检测循环成骨细胞祖细胞并评估成骨细胞分化的表达 基因.高级糖尿病和脂质代谢方面的培训将使金博士能够解释这些发现， 对糖尿病性骨病的发病机制有重要的认识。这项研究有望取得进展 了解骨髓脂肪行为，这可能会导致有针对性的预防和治疗策略， 糖尿病性骨病和骨质疏松症。金博士组建了一个多元化的导师团队， 骨质疏松症、新陈代谢、流行病学、生物统计学和放射学方面的专家。她的训练将包括 结合个人教程与她的导师和科学顾问，动手经验，和正式的 课程作业拟议的研究将为Kim博士提供更大和更长期的初步数据。 糖尿病性骨病的前瞻性研究，她将在提交的Merit Review申请中提出 在CDA-2期间结束之前。金博士致力于改善退伍军人的医疗保健， 临床研究，并与她提出的研究和培训，她将制定一个蓬勃发展的研究计划，在 退伍军人事务部