The effects of type 1 diabetes on bone health in children and adolescents

 描述（由申请人提供）：1型糖尿病（T1 DM）导致严重的骨骼脆弱性。T1 DM成人的髋部骨折率几乎是普通人群的6倍。这种骨折风险增加的病理生理学仍然知之甚少，阻碍了预防骨折及其显著相关发病率和死亡率的努力。临床研究以及动物模型研究表明，T1 DM导致骨形成抑制，这一过程在青春期生长突增期达到峰值。这些观察结果表明，儿童/青春期是骨骼特别容易受到糖尿病影响的关键时期。因此，该提案旨在进一步表征糖尿病性骨病，重点关注儿童生长期间的影响。我们将前瞻性地随访一组T1 DM儿童和匹配的对照组2年，并评估糖尿病对骨生成、骨骼微结构和骨强度估计值的影响。我们将确定血糖控制和糖尿病相关代谢紊乱（包括胰岛素样生长因子1浓度降低）对这些指标的影响程度。这些研究将利用几种互补的成像方式，包括DXA和高分辨率外周定量CT和个体小梁分割的新技术。米切尔博士是哈佛医学院的儿科讲师和马萨诸塞州总医院儿科内分泌科的儿科助理。她的长期目标是成为儿科骨生理学领域的独立临床研究者，利用骨骼评估的传统和研究方法来了解早期生命因素对长期骨骼健康的影响，重点关注T1 DM的影响。她在健康儿童骨矿物质代谢临床研究方面的经验使她能够很好地领导这个项目。她的职业发展将由她的共同导师Madhusmita Misra，玛丽Bouxsein和Enrico Cagliero博士密切指导，他们共同提供儿童骨增长的激素决定因素，骨生物力学，研究成像技术和糖尿病病理生理学方面的专业知识。他们在指导初级研究人员方面有着出色的记录，并致力于米切尔博士的成功。拟议项目的执行将为Mitchell博士提供骨健康评估的生化和放射技术方面的实践培训。此外，职业发展计划还包括哈佛公共卫生学院高级生物统计学和研究设计的正式指导。这个指导研究奖将为米切尔博士提供额外的培训，这对她作为儿科骨生理学和儿童骨质疏松症前因的独立临床研究者的成功至关重要。进一步了解T1 DM对骨健康的有害影响对于设计后续干预性试验以优化T1 DM患者的骨健康至关重要。

 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 be critical to the design of subsequent interventional trials to optimize bone health in patients with T1DM.