DESCRIPTION (provided by applicant): Type 1 diabetes (T1DM) leads to profound skeletal fragility. Adults with T1DM have a hip fracture rate almost 6-fold higher than the general population. The pathophysiology of this increased fracture risk remains poorly understood, hampering efforts to prevent fractures and their significant associated morbidity and mortality. Clinical studies as well as studies in animal models have demonstrated that T1DM leads to suppression of bone formation, a process which peaks during the pubertal growth spurt. These observations suggest that childhood/adolescence is a critical period during which the skeleton is particularly vulnerable to the effects of diabetes. This proposal thus seeks to further characteriz diabetic bone disease with a focus on effects during childhood growth. We will prospectively follow a cohort of children with T1DM and matched controls for 2 years and evaluate the effects of diabetes on bone accrual, skeletal microarchitecture, and estimates of bone strength. We will determine to what extent glycemic control and diabetes-associated metabolic derangements including decreased insulin-like growth factor 1 concentrations affect these measures. These studies will utilize several complementary imaging modalities including DXA and the novel techniques of high-resolution peripheral quantitative CT and individual trabecula segmentation. Dr. Mitchell is an Instructor in Pediatrics at Harvard Medical School and an Assistant in Pediatrics in the Pediatric Endocrine Unit at Massachusetts General Hospital. Her long-term goal is to be an independent clinical investigator in the field of pediatric bone physiology, utilizing both traditional and investigational methods of skeletal assessment to understand the influence of early life factors on long-term bone health with a focus on the effects of T1DM. Her experience in clinical studies of bone mineral metabolism in healthy children equips her well to lead this project. Her career development will be closely guided by her co-mentors, Drs. Madhusmita Misra, Mary Bouxsein, and Enrico Cagliero, who jointly provide expertise in hormonal determinants of bone accrual in children, bone biomechanics, investigational imaging technologies, and diabetes pathophysiology. They have an outstanding track record of mentoring junior investigators and are committed to Dr. Mitchell's success. Execution of the proposed project will provide Dr. Mitchell hands-on training in biochemical and radiological techniques of bone health assessment. In addition, the career development plan incorporates formal instruction in advanced biostatistics and study design at the Harvard School of Public Health. This mentored research award will provide Dr. Mitchell the additional training critical to her success as an independent clinical investigator in pediatric bone physiology and childhood antecedents of osteoporosis. Improved understanding of the deleterious effects of T1DM on bone health will...