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: 10413813
• 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/10413813
• 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; 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; Persons; 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; Veterans Health Administration; X-Ray Computed Tomography; adult obesity; bariatric surgery; bone; bone fracture repair; bone health; bone imaging; bone mass; bone quality; bone turnover; design; diabetic bone disease; economic cost; effective therapy; experience; falls; fracture risk; glycemic control; 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.

Kim博士的长期目标是成为VA物理研究者，阐明糖尿病骨的机制 疾病以减少糖尿病患者的骨折风险。人们越来越认识到骨病 是2型糖尿病（T2DM）的并发症。在T2DM中，髋部骨折风险增加了 第三，骨折后，患有T2DM的个体的术后并发症发生率较高，较高 死亡风险。即使在控制跌倒后，骨折风险也会增加，并且髋部骨折发生了 保留或更高的骨矿物质密度（BMD）。提议骨髓中的脂肪发挥 致病作用在糖尿病骨病中，因为脂肪和骨头在骨髓中密切相关 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，并且 脂肪形成可能以骨基细胞生成为代价。实际上，骨髓脂肪含量更高 与较低的BMD和较高的断裂风险有关。但是，尚不清楚骨髓脂肪是否可以 操纵以改善糖尿病骨病。血红蛋白A1C（HBA1C）与较高的 骨髓脂肪的水平，因此血糖控制增强可能会使骨髓脂肪正常化并改善骨骼结局。 鉴于糖尿病的宽度患病率以及骨折的医疗和经济成本，有一个 迫切需要了解糖尿病骨病，以识别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 实施了解改善血糖控制对骨髓脂肪和骨骼的影响所需的研究 健康。她将获得有价值的临床研究和翻译方法的专业知识，将她定位为 成为糖尿病骨病领域的领导者。金博士将入学并关注75名退伍军人 与临床医生合作以改善血糖控制的受控T2DM（HBA1C 8.5-12.0％）。她会的 确定改善血糖控制对骨髓脂肪的影响（AIM 1）以及 骨髓脂肪随骨质量和质量的变化（AIM 2）。追求这些目标将涉及批判性培训 前瞻性队列研究的设计和实施。金博士将使用高级和敏感的成像 模态（包括磁共振光谱，高分辨率外围定量计算 层析成像）评估基线时骨髓脂肪和骨骼结局，然后经过一年的严格医疗 管理。 Kim博士还将使用尖端翻译方法探索成骨细胞的作用 分化是连接骨髓脂肪和骨骼结局的途径（AIM 3）。这将包括表征 通过流式细胞术和评估成骨细胞分化的表达来循环成骨细胞祖细胞 基因。接受晚期糖尿病和脂质代谢的培训将使Kim博士可以解释这些发现和 对糖尿病骨病的发病机理获得重要的见解。这项研究有望进步 了解骨髓脂肪行为，这可能会导致针对性的预防和治疗策略 糖尿病骨病和骨质疏松症。金博士组建了一个分歧 骨质疏松，代谢，流行病学，生物统计学和放射学专家。她的培训将涉及 个人教程与她的导师和科学顾问，动手经验以及以前的结合 课程。拟议的研究将为Kim博士提供较大和长期的初步数据 糖尿病骨病的前瞻性研究，她将在提交的优异审查申请中提出 在CDA-2期结束之前。金博士致力于通过 临床研究以及她提出的研究和培训，她将在 VA。