Bone marrow fat and skeletal health in type 2 diabetes

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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.