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: 10657381
• 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/10657381
• 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; 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; 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; clinical translation; 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.

金博士的长期目标是成为一名退伍军人管理局医师调查员，阐明糖尿病骨的机制

项目成果

The Interaction of Acute-Phase Reaction and Efficacy for Osteoporosis After Zoledronic Acid: HORIZON Pivotal Fracture Trial.

• DOI: 10.1002/jbmr.4434
• 发表时间: 2022-01
• 期刊: JOURNAL OF BONE AND MINERAL RESEARCH
• 影响因子: 6.2
• 作者: Black, Dennis M.;Reid, Ian R.;Napoli, Nicola;Ewing, Susan K.;Shiraki, Masataka;Nakamura, Toshitaka;Takeuchi, Yasuhiro;Schafer, Anne L.;Kim, Tiffany Y.;Cauley, Jane A.
• 通讯作者: Cauley, Jane A.