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

摘要/摘要 在儿童肥胖症流行的同时，儿童中的2型糖尿病(T2D)正成为一个重要的公众 健康问题。在过去的十年里，儿童T2D的发病率增加了50%，最近的数据显示 T2D占儿童新诊断糖尿病病例的四分之一。患有T2D的儿童有攻击性 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 在很小的时候就有因素。这种疾病的特点是胰岛素抵抗和胰岛素分泌受损，但 T2D的分子基础尚未完全阐明。这项研究旨在揭示精氨酸的作用。 代谢在儿童T2D发病中的作用及外源性精氨酸对β细胞的影响 T2D儿童的功能障碍。精氨酸是一种已知的刺激胰腺β细胞分泌胰岛素的物质。一氧化氮 (NO)是由精氨酸通过一氧化氮合酶合成的，精氨酸在这两种途径中刺激胰岛素的分泌。 以及通过刺激鸟苷环化酶、膜去极化和代谢的NO依赖机制 副产品。精氨酸对胰腺β细胞的作用依赖于细胞内可利用的精氨酸 集中精神。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 确定“细胞内”精氨酸利用率的机会及其在多种途径中的相对贡献 这个泳池。在成人T2D患者中的此类研究表明，精氨酸和NO在T2D的发病机制中发挥作用。 T2D通过影响胰岛素分泌和胰岛素敏感性。在T2D种群的子集中，即具有 我们的研究小组发现，患有酮症倾向糖尿病(KPD)的成年人具有独特的代谢特征，即 高血糖时“细胞内”精氨酸利用率显著降低。此外，它们的胰岛素分泌 给予精氨酸后，反应恢复。在我对患有T2D的儿童的初步数据中，我发现 他们的代谢特征与成人KPD相似。具体地说，患有T2D的儿童禁食时间较低 精氨酸、瓜氨酸(精氨酸前体)和谷氨酰胺(瓜氨酸前体)水平。在这项提议中，我将寻求 对这些产生假说的观察进行动力学验证，以调查精氨酸代谢在 儿科T2D。我的中心假设是，患有T2D的儿童精氨酸供应不足(目标1)， 导致次优β细胞功能，可通过外源性精氨酸注射恢复(目标2)。如果我的 假设得到证实，补充精氨酸将在改善糖尿病预后方面发挥重要的临床作用 在这个群体中作为一种安全、低成本和容易获得的营养。我非常适合进行这项研究 考虑到我以前的临床和研究经验，以及我接触到大量的患者， 得克萨斯儿童医院和贝勒医学院拥有强大的指导团队。穿过 这个职业发展奖，我将获得宝贵的经验，在最先进的运动技术使用 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.