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内科研究员，阐明糖尿病骨骼的发病机制 以降低糖尿病患者的骨折风险。越来越多的人认识到骨病 是2型糖尿病(T2 DM)的并发症。在T2 DM患者中，髋部骨折的风险增加超过1 第三，在骨折后，T2 DM患者的术后并发症发生率更高， 死亡的风险。即使在控制跌倒之后，骨折风险也会增加，尽管 保持或更高的骨密度(BMD)。骨髓中的脂肪被认为是一种 在糖尿病骨疾病中的致病作用，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共享共同的间充质干细胞前体，并且 脂肪生成可能以成骨细胞生成为代价。事实上，骨髓脂肪含量更高 与较低的骨密度和较高的骨折风险有关。然而，目前尚不清楚骨髓脂肪能否 被操纵以改善糖尿病骨骼疾病。血红蛋白A1c(HbA1c)与 骨髓脂肪水平，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。 鉴于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骨疾病，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和 实施必要的研究，以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翻译方法方面的专业知识，这将使她 成为糖尿病骨病领域的领先者。金博士将招收并跟踪75名退伍军人 受控的T2 DM(HbA1c 8.5-12.0%)，他们正在与临床医生合作改善血糖控制。她会的 确定改善血糖控制对骨髓脂肪的影响(目标1)及其与 骨髓脂肪随骨质量和骨量的变化(目标2)。追求这些目标将涉及关键的培训 前瞻性队列研究的设计和实施。金博士将使用先进和灵敏的成像技术 模式(包括磁共振波谱、高分辨率外设定量计算 体层摄影术)以评估基线和强化治疗一年后的骨髓脂肪和骨骼结果 管理层。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(目标3)。这将包括刻画 流式细胞术检测成骨细胞前体细胞及其在成骨细胞分化中的表达 基因。高级糖尿病和脂代谢方面的培训将使金博士能够解释这些发现并 获得对糖尿病骨病发病机制的重要见解。这项研究有望取得进展 了解骨髓脂肪的行为，这可能导致有针对性的预防和治疗策略 糖尿病骨病和骨质疏松症。金博士组建了一个多元化的导师团队，成员包括 骨质疏松症、新陈代谢、流行病学、生物统计学和放射学专家。她的培训将包括 与她的导师和科学顾问的个人教程、实践经验和正式教程相结合 课程作业。这项拟议的研究将为金博士提供更大、更长期的初步数据 糖尿病骨疾病的前瞻性研究，她将在提交的功绩审查申请中提出这项研究 在CDA-2期间结束之前。金博士致力于通过以下方式改善退伍军人的医疗保健 临床研究，以及她提议的研究和培训，她将在 退伍军人事务部。