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

 描述(申请人提供)：1型糖尿病(T1 DM)会导致严重的骨骼脆弱。患有T1 DM的成年人髋部骨折的发生率几乎是普通人群的6倍。这种增加的骨折风险的病理生理学机制仍然知之甚少，阻碍了预防骨折及其显著相关的发病率和死亡率的努力。临床研究和动物模型研究表明，T1 DM导致抑制骨形成，这一过程在青春期生长激增时达到顶峰。这些观察表明，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，这项建议寻求进一步描述糖尿病骨骼疾病的特征，重点放在儿童成长期间的影响上。我们将前瞻性地跟踪一组患有T1 DM的儿童和匹配的对照组2年，评估糖尿病对骨积累、骨骼微结构和骨强度估计的影响。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和单个小梁分割的新技术。米切尔医生是哈佛医学院的儿科学讲师，也是马萨诸塞州总医院儿科内分泌科的助理。她的长期目标是成为儿科骨生理学领域的独立临床研究员，利用骨骼评估的传统和调查方法了解早期生活因素对长期骨健康的影响，重点是T1 DM的影响。她在健康儿童骨矿代谢的临床研究中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博士、Mary Bouxsein博士和Enrico Cagliero博士密切指导，他们共同提供儿童骨积累的荷尔蒙决定因素、骨生物力学、调查成像技术和糖尿病病理生理学方面的专业知识。他们在指导初级调查人员方面有着出色的记录，并致力于米切尔博士的成功。拟议项目的实施将为米切尔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，职业发展计划纳入了哈佛公共卫生学院高级生物统计学和研究设计的正式教学。这一指导研究奖将为米切尔博士提供额外的培训，这对她作为一名儿科骨生理学和儿童骨质疏松先兆的独立临床研究员的成功至关重要。更好地了解T1 DM对骨健康的有害影响将是设计后续干预试验以优化T1 DM患者骨健康的关键。

 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.