Investigation of Arginine Metabolism and Its Effects on Beta Cell Function in Children with Type 2 Diabetes

总结/摘要 与儿童肥胖症的流行同时，儿童2型糖尿病（T2 D）正在成为一个重要的公众问题。 健康问题。在过去十年中，儿童T2 D的发病率增加了50%，最近的数据显示， T2 D占儿童新诊断糖尿病病例的四分之一。患有T2 D的儿童具有攻击性 病程和β细胞功能迅速下降，许多人还具有多种心血管疾病的风险 早期的因素。这种疾病的特征是胰岛素抵抗和胰岛素分泌受损，但 T2 D的分子基础尚未完全阐明。本研究旨在揭示精氨酸的作用 代谢在儿童2型糖尿病发病机制中的作用及外源性精氨酸对β细胞的影响 T2 D儿童的功能。精氨酸是胰腺β细胞中胰岛素分泌的已知刺激物。一氧化氮 (NO)由精氨酸通过NO合酶合成，精氨酸刺激NO介导的胰岛素分泌和NO介导的胰岛素分泌。 和NO的非依赖性机制，通过刺激鸟苷酸环化酶，膜去极化，和代谢 副产品。精氨酸对胰岛β细胞的作用依赖于细胞可利用的精氨酸 浓度.使用同位素示踪剂输注和靶向代谢组学的动力学技术提供了独特的 有机会确定“细胞内”精氨酸的可用性和各种途径的相对贡献， 这个游泳池在患有T2 D的成人中的此类研究已经表明精氨酸和NO在T2 D的发病机制中起作用。 2型糖尿病通过影响胰岛素分泌和胰岛素敏感性。在T2 D人群的一个子集中，即， 我们的研究小组发现，KPD成人患者有一个独特的代谢组学特征， 在高血糖期间“细胞内”精氨酸利用率显著降低。此外，它们的胰岛素分泌 在精氨酸给药后反应恢复。在我对T2 D儿童的初步数据中，我发现 与成人KPD患者的代谢特征相似。具体而言，T2 D儿童的空腹血糖较低， 精氨酸、瓜氨酸（精氨酸前体）和谷氨酰胺（瓜氨酸前体）水平。在这个提议中，我将寻求 动力学验证这些假设产生的观察，以调查精氨酸代谢的作用， 儿科T2 D。我的中心假设是T2 D儿童的精氨酸可用性不足（目标1）， 导致β-细胞功能不佳，这可以通过外源性精氨酸施用来恢复（目的2）。如果我的 假设得到证实，精氨酸补充剂将在改善糖尿病结局方面发挥重要作用 作为一种安全、低成本和容易获得的营养素。我非常适合进行这项研究 鉴于我以前的临床和研究经验，以及我接触大量患者的机会， 资源，并在得克萨斯州儿童医院和贝勒医学院强大的导师团队。通过 这个职业发展奖，我将获得宝贵的经验，在国家的最先进的动力学技术，使用 稳定同位素示踪剂和儿童靶向代谢组学以及生物统计学和数据分析。

Summary/Abstract In parallel with the childhood obesity epidemic, type 2 diabetes (T2D) in children is becoming a significant public health concern. The incidence of pediatric T2D increased by 50% during the past decade, and recent data show T2D accounts for one in four newly-diagnosed diabetes cases in children. Children with T2D have an aggressive disease course and a rapid decline in β-cell function, and many also have multiple cardiovascular disease risk factors at an early age. The disease is characterized by insulin resistance and impaired insulin secretion, but the molecular underpinnings of T2D are not yet fully elucidated. This study aims to uncover the role of arginine metabolism in the pathogenesis of pediatric T2D and the effect of exogenous arginine administration on β-cell function in children with T2D. Arginine is a known stimulant of insulin secretion in pancreatic β-cells. Nitric oxide (NO) is synthesized from arginine by NO synthase, and arginine stimulates insulin secretion in both NO-mediated and NO-independent mechanisms by stimulating guanylate cyclase, membrane depolarization, and metabolic by-products. The effects of arginine in pancreatic β-cells are dependent on the cells’ available arginine concentration. Kinetic techniques using isotope tracer infusions and targeted metabolomics provide a unique opportunity to determine “intracellular” arginine availability and its relative contribution of various pathways to this pool. Such studies in adults with T2D have shown that arginine and NO play roles in the pathogenesis of T2D by affecting insulin secretion and insulin sensitivity. In a subset of the T2D population, namely, those with ketosis-prone diabetes (KPD), our group found that adults with KPD had a unique metabolomic signature with a significant reduction in “intracellular” arginine availability during hyperglycemia. Moreover, their insulin secretory responses were restored following arginine administration. In my preliminary data in children with T2D, I found a similar metabolic signature in them to that of adults with KPD. Specifically, children with T2D had lower fasting arginine, citrulline (arginine precursor), and glutamine (citrulline precursor) levels. In this proposal, I will seek kinetic validation of these hypothesis-generating observations to investigate the role of arginine metabolism in pediatric T2D. My central hypothesis is that children with T2D have inadequate arginine availability (Aim 1), leading to suboptimal β-cell function, which can be restored by exogenous arginine administration (Aim 2). If my hypotheses are proven, arginine supplementation will play a clinically vital role in improving diabetes outcomes in this population as a safe, low-cost, and readily available nutrient. I am uniquely suited to conduct this study given my previous clinical and research experience, as well as my access to a large patient population, a wealth of resources, and strong mentorship team at Texas Children’s Hospital and Baylor College of Medicine. Through this Career Development Award, I will gain invaluable experience in state-of-the-art kinetic techniques using a stable isotope tracer and targeted metabolomics in children, as well as in biostatistics and data analysis.