Serotonin as a Novel Biomarker for Progression to Type 2 Diabetes in Obese Adolescents

项目总结： 2型糖尿病(T2D)是一种世界性的流行病，影响着近3亿成年人，而且 儿童的数量，对个人和社区的健康产生深远的影响。年估计的糖尿病成本 美国现在已经超过了2000亿美元。它是致盲、截肢和终末期的主要原因。 肾脏疾病，也是心肌梗塞和中风的主要原因。T2D的两个主要决定因素 肥胖与胰岛素抵抗(IR)有关，但T2D的发病机制尚不清楚。只有一半 肥胖儿童中IR的比例要低得多，进展为T2D的比例要低得多。为什么一些肥胖儿童避免新陈代谢 当其他人发展成T2D时，功能障碍是对T2D发病机制的理解的一个关键差距，并排除 设计和实施糖尿病预防和治疗方案。我的长期职业目标是 建立一个独立的研究计划，致力于识别和治疗肥胖儿童的最高风险 用于IR和T2D。使用最先进的血浆样本代谢组图谱，我们之前发现 儿童IR与支链氨基酸(BCAA)水平升高有关。最近我们有 使用了24小时尿样的代谢图谱，其优势是整合了不同的 随着时间的推移非侵入性的代谢状态。我们发现尿中5-羟基吲哚乙酸(5-羟基吲哚乙酸，5-羟基吲哚乙酸)的排泄量减少。 HIAA)，5-羟色胺的主要代谢物，作为一个新的生物标志物与肥胖青年的T2D相关。这一发现 特别有趣的是，5-羟色胺可以增加胰腺β细胞的复制、β细胞的质量和血糖- 刺激胰岛素分泌。T2D中5HIAA的减少可能反映了细胞内5-羟色胺的减少 可用性，因为：(A)升高的支链氨基酸与5-羟色胺的前体色氨酸竞争摄取进入β细胞 和其他组织；以及(B)在肥胖中，色氨酸代谢受到失调，并转向产生 犬尿氨酸而不是血清素。这些发现表明，色氨酸可获得性和5-羟色胺的减少 生产通过抑制胰岛素分泌、促进进展而参与糖尿病的发病。 从肥胖到糖耐量低减和T2D。我们假设5-羟色胺和5-羟色胺的代谢物 包括5-HIAA构成了预测肥胖青年T2D发生的有用的尿液生物标志物。这 假设将在三个具体目标中得到检验。目标1将识别不同的尿液代谢特征 在患有和不患有T2D的非肥胖和肥胖儿童中。目标2将确定这些尿液代谢是否 信号与葡萄糖耐量和血糖控制参数相关。目标3将确定尿液 在基线或随访期间测量的5-HIAA预测倾向指数的变化，这是一种综合衡量 β细胞功能在没有T2D的瘦身和肥胖者的纵向研究中的应用。我的指导团队，其中包括 克里斯托弗·纽加德博士(科学导师)和迈克尔·弗里马克博士(学术导师)将提供指导 以及临床研究中的定量和方法学专长。在杜克大学的杰出研究中 作为一名学院派儿科内分泌学家，这个奖项将有助于我向独立的方向过渡。

PROJECT SUMMARY: Type 2 diabetes (T2D) is a worldwide pandemic affecting nearly 300 million adults and a rapidly increasing number of children, with profound individual and community health consequences. Estimated diabetes costs in the United States now exceed $200 billion. It is the major cause of blindness, leg amputation, and end-stage kidney disease and a principal cause of myocardial infarction and stroke. The two major determinants of T2D are obesity and insulin resistance (IR), yet the pathogenesis of T2D remains poorly understood. Only one-half of obese children are IR, and a far lower percentage progress to T2D. Why some obese children avoid metabolic dysfunction while others develop T2D is a critical gap in in the understanding of T2D pathogenesis and precludes the design and implementation of programs for diabetes prevention and treatment. My long-term career goal is to establish an independent research program dedicated to identifying and treating obese children at highest risk for IR and T2D. Using state-of-the-art metabolomic profiling of plasma samples, we previously found that childhood IR is associated with increased levels of the branch-chain amino acids (BCAA). Recently we have employed metabolic profiling of 24-hour urine samples, which has the advantage of integrating differences in metabolic status over time non-invasively. We identified a decrease in urine 5-Hydroxyindoleacetic acid (5- HIAA), the major metabolite of serotonin, as a novel biomarker associated with T2D in obese youth. This finding is particularly interesting given that serotonin increases pancreatic β-cell replication, β-cell mass, and glucose- stimulated insulin secretion. The reduction in 5HIAA in T2D likely reflects a decrease in cellular serotonin availability, since: (a) elevated BCAA compete with tryptophan, the precursor of serotonin, for uptake into β-cells and other tissues; and (b) in obesity, tryptophan metabolism is dysregulated and shifted towards production of kynurenine rather than serotonin. These findings suggest that reductions in tryptophan availability and serotonin production contribute to diabetes pathogenesis through inhibition of insulin secretion, promoting progression from obesity to glucose intolerance and T2D. We hypothesize that serotonin and serotonin metabolites including 5-HIAA constitute useful urine biomarkers that predict development of T2D in obese youth. This hypothesis will be tested in three Specific Aims. Aim 1 will identify urinary metabolic signatures that differ among non-obese and obese children with and without T2D. Aim 2 will determine if these urinary metabolic signatures correlate with parameters of glucose tolerance and glycemic control. Aim 3 will determine if urinary 5-HIAA measured at baseline or during follow-up predicts changes in disposition index, a composite measure of β-cell function in a longitudinal study of lean and obese subjects without T2D. My mentoring team, which includes Drs. Christopher Newgard (scientific mentor) and Michael Freemark (academic mentor), will provide guidance and quantitative and methodological expertise in clinical research. With an outstanding Duke University research environment, this award will facilitate my transition to independence as an academic pediatric endocrinologist.