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

项目概要： 2型糖尿病（T2 D）是一种世界性的流行病，影响近3亿成年人，并且在全球范围内迅速增加。 儿童数量，对个人和社区健康产生深远影响。估计糖尿病费用 美国现在超过2000亿美元。它是导致失明、截肢和晚期癌症的主要原因。 肾脏疾病和心肌梗塞和中风的主要原因。T2 D的两个主要决定因素 肥胖和胰岛素抵抗（IR），但T2 D的发病机制仍然知之甚少。只有一半 的肥胖儿童是IR，并且进展为T2 D的百分比要低得多。为什么有些肥胖儿童避免代谢 在理解T2 D发病机制方面存在关键差距， 糖尿病预防和治疗方案的设计和实施。我的长期职业目标是 建立一个独立的研究项目，致力于识别和治疗肥胖儿童的最高风险 对于IR和T2 D。使用最先进的血浆样本代谢组学分析，我们以前发现， 儿童IR与支链氨基酸（BCAA）水平升高有关。最近我们 采用24小时尿液样本的代谢分析，其优点是整合了 随着时间推移的代谢状态。我们发现尿5-羟基吲哚乙酸（5-羟吲哚乙酸）减少， HIAA），5-羟色胺的主要代谢产物，作为一种新的生物标志物与T2 D在肥胖的青年。这一发现 特别有趣的是，血清素增加胰腺β细胞复制，β细胞质量和葡萄糖- 刺激胰岛素分泌。T2 D中5 HIAA的减少可能反映了细胞5-羟色胺的减少 可用性，因为：（a）升高的BCAA与色氨酸（5-羟色胺的前体）竞争β细胞的摄取 和（B）在肥胖症中，色氨酸代谢失调并转向产生 犬尿氨酸而不是血清素。这些发现表明，色氨酸的可用性和血清素的减少 生产有助于糖尿病的发病机制，通过抑制胰岛素分泌，促进进展 从肥胖到葡萄糖耐受不良和2型糖尿病。我们假设血清素和血清素代谢物 包括5-HIAA在内的尿生物标志物构成了预测肥胖青年中T2 D发展的有用的尿生物标志物。这 假设将在三个具体目标中进行检验。目标1将确定尿代谢签名， 在非肥胖和肥胖儿童中，有和没有T2 D。目标2将确定这些尿液代谢是否 特征与葡萄糖耐量和血糖控制参数相关。目标3将确定是否尿 5-在基线或随访期间测量的HIAA可预测处置指数的变化，处置指数是 无T2 D的瘦型和肥胖受试者的纵向研究中的β细胞功能。我的指导团队，其中包括 Drs. Christopher Newgard（科学导师）和Michael Freemark（学术导师）将提供指导 以及临床研究的定量和方法学专业知识。凭借杜克大学杰出的研究成果 环境，这个奖项将促进我过渡到独立作为一个学术儿科内分泌学家。

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.