Dyslipidemia and CV Risk Factors in Pediatric Obesity and Type 2 Diabetes

描述(由申请人提供)：Sheela N.Magge博士是一名儿科内分泌学家，接受过临床流行病学硕士学位培训，在面向患者的研究中表现出对学术生涯的持续承诺。她现在计划扩大她在儿童肥胖症和2型糖尿病(T2 DM)方面的研究兴趣，以包括他们的心血管并发症。那里 目前缺乏关于青少年的最佳血脂水平以及哪些青少年心血管疾病(CVD)风险最高的科学证据。马格博士计划在宾夕法尼亚大学心脏科的丹尼尔·雷德博士以及共同导师查尔斯·斯坦利和埃米尔·莫勒博士的指导下，获得儿童肥胖症和2型糖尿病中血脂异常和心血管疾病风险方面的专业知识。该提案的研究计划是一项对4组青春期青少年的观察性队列研究，年龄在12-17岁之间：瘦对照组(LC)、肥胖胰岛素敏感组(OIS)、肥胖胰岛素抵抗组(OIR)和肥胖伴T2 DM组(OT2)。这些小组将有助于区分肥胖、胰岛素抵抗和导致高血糖的胰岛素分泌缺陷的影响。本研究的主要目的(横断面)是：1.比较4组的血脂谱，描述血脂异常与胰岛素抵抗(静脉葡萄糖耐量试验测量)的关系；2.比较CIMT测量的亚临床动脉粥样硬化，其次是4组的臂部反应性(FMD)测量的内皮功能障碍；3.确定哪些炎症介质和/或脂肪细胞因子与这些青少年早期动脉粥样硬化(CIMT)的存在有关。次要目标(预期)是调查的探索性目标。)CIMT和FMD在两组中是否进展超过2年，以及哪种血脂水平、炎症介质和/或脂肪因子最能预测早期动脉粥样硬化的进展(CIMT的变化)。很少有儿科研究使用这些技术，也没有报道肥胖和T2 DM儿童的纵向CIMT数据。在获奖期间，Magge博士还制定了一项全面的教育计划，以获得在这一人群中学习血脂异常、炎症标志物和非侵入性成像使用方面的专业知识。她的目标是确定那些心血管疾病风险最高的青少年，他们将从未来的管理和治疗试验中受益。拟议中的项目将培训马格博士成为一名独立的、以患者为导向的研究人员。公共卫生相关性：目前儿童肥胖的流行，导致儿童时期的T2 DM和代谢综合征，使血脂异常和未来发生心血管疾病的风险成为儿科严重关注的问题。随着越来越多的儿童患上肥胖症、2型糖尿病和血脂异常，他们很可能比现在的成年人更早几十年成为患心血管疾病的风险人群。这将造成巨大的人员伤亡和公共卫生负担。儿科医生在儿童时期学会处理这种风险是至关重要的。

DESCRIPTION (provided by applicant): Dr. Sheela N. Magge is a pediatric endocrinologist with Masters degree training in Clinical Epidemiology, who has shown a sustained commitment to an academic career in patient-oriented research. She now plans to extend her research interests in pediatric obesity and type 2 diabetes (T2DM) to include their cardiovascular complications. There is a current dearth of scientific evidence as to what optimal lipid levels are in adolescents, and which adolescents are at the highest cardiovascular disease (CVD) risk. Dr. Magge plans to gain expertise in the area of dyslipidemia and CVD risk in childhood obesity and type 2 diabetes, under the mentorship of Dr. Daniel Rader of the Division of Cardiology at the University of Pennsylvania, and co-mentors, Drs. Charles Stanley and Emile Mohler. The proposal's research plan is an observational cohort study of 4 groups of pubertal adolescents, ages 12-17 years: lean controls (LC), obese insulin sensitive (OIS), obese insulin resistant (OIR), and obese with T2DM (OT2). These groups will help to differentiate between the effects of obesity, insulin resistance, and insulin secretory defects causing hyperglycemia. The primary aims (cross-sectional) of the study are: 1. to compare the lipid profiles of the 4 groups and delineate the relationship between dyslipidemia and insulin resistance (measured by intravenous glucose tolerance test), 2. to compare subclinical atherosclerosis as measured by CIMT, and secondarily, endothelial dysfunction as measured by brachial reactivity (FMD), in the 4 groups, 3. to identify which inflammatory mediators and/or adipocytokines correlate with the presence of early atherosclerosis (CIMT) in these adolescents. The secondary aim (prospective) is an exploratory aim to investigate a.) whether CIMT and FMD progress over 2 years in the groups, and b.) which lipid levels, inflammatory mediators, and/or adipokines best predict the progression of early atherosclerosis (change in CIMT). Few pediatric studies have used these techniques, and none have reported longitudinal CIMT data in obese and T2DM children. Dr. Magge has also developed a comprehensive educational plan during the award period, to gain expertise in dyslipidemia, inflammatory markers, and the use of non-invasive imaging in this population. Her goal is to identify those adolescents at the highest CVD risk, who would benefit from future management and treatment trials. The proposed project will train Dr. Magge for a career as an independent, patient-oriented researcher. Public health relevance: The current epidemic of pediatric obesity, leading to T2DM and the metabolic syndrome during childhood, have made dyslipidemia and the risk of future CVD serious concerns in pediatrics. As more children develop obesity, T2DM, and dyslipidemia, they are likely to become a population at risk for developing CVD decades earlier than adults today. This will represent a tremendous human toll and public health burden. It is vital that pediatricians learn to address this risk during childhood.