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

2 型糖尿病儿童精氨酸代谢及其对 β 细胞功能影响的研究

• 批准号: 10526016
• 负责人: Mustafa Tosur
• 金额: $ 18.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10526016
• 关键词: Acute; Address; Adult; Affect; Age; Arginine; Beta Cell; Biometry; Bolus Infusion; Cell membrane; Cell physiology; Cells; Child; Childhood; Childhood diabetes; Citrulline; Clinical; Clinical Research; Clinical Trials; Closure by clamp; Coupled; Data; Data Analyses; Defect; Development Plans; Diabetes Mellitus; Dietary intake; Disease; Etiology; Fasting; Funding; Glutamine; Goals; Guanylate Cyclase; Health Care Costs; Hyperglycemia; Impairment; Incidence; Infusion Technique; Infusion procedures; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intravenous; Investigation; Isotopes; K-Series Research Career Programs; Kinetics; Knowledge; Mass Spectrum Analysis; Mediating; Medicine; Membrane; Mentorship; Metabolic; Metabolic Pathway; Metabolism; Molecular; Newly Diagnosed; Nitric Oxide; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; OGTT; Obesity Epidemic; Oral; Outcome; Pathogenesis; Pathway interactions; Patients; Pediatric Hospitals; Plasma; Play; Population; Process; Production; Public Health; Research; Resources; Risk Factors; Role; Stimulant; Structure of beta Cell of islet; Suggestion; Supplementation; Techniques; Testing; Texas; Tracer; Training; Validation; Vulnerable Populations; amino acid metabolism; arginase; cardiovascular disorder risk; career development; college; cost; experience; experimental study; future implementation; glycemic control; improved; insulin secretion; insulin sensitivity; metabolomics; minimally invasive; obesity in children; oxidation; patient population; response; stable isotope; tool; type 2 diabetes in children

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.

摘要/摘要 与儿童肥胖流行同时，儿童中的2型糖尿病（T2D）正在成为重要的公众 健康问题。在过去的十年中，小儿T2D的事件增加了50％，最近的数据显示 T2D在儿童中解释了四分之一的新诊断的糖尿病病例。 T2D的孩子有进取心 疾病病程和β细胞功能迅速下降，许多人也具有多种心血管疾病风险 在很小的时候。该疾病的特征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。这项研究旨在发现精氨酸的作用 小儿T2D发病机理的代谢和外源精氨酸对β细胞的影响 T2D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性。一氧化氮 （NO）通过非合酶从精氨酸中合成，精氨酸刺激两个NO介导的胰岛素分泌 通过刺激鸟苷酸环化酶，膜去极化和代谢来实现无独立的机制 副产品。精氨酸在胰腺β细胞中的影响取决于细胞的可用精氨酸 专注。使用同位素示踪剂输注和靶向代谢组学提供了独特的动力学技术 确定“细胞内”精氨酸可用性及其各种途径相对贡献的机会 这个游泳池。 T2D成年人的此类研究表明，精氨酸和没有发挥作用 T2D通过影响胰岛素分泌和胰岛素敏感性。在T2D人群的一个子集中，即 酮症容易发挥的糖尿病（KPD），我们的小组发现，具有KPD的成年人具有独特的代谢组学特征 高血糖期间“细胞内”精氨酸的可用性显着降低。而且，他们的胰岛素分泌 精氨酸给药后恢复了反应。在我的T2D儿童的初步数据中，我发现 它们的代谢签名与具有KPD的成年人的签名。具体来说，患有T2D的孩子的禁食较低 精氨酸，柑橘类（精氨酸前体）和谷氨酰胺（citrullline前体）水平。在此提案中，我将寻求 这些假设生成的观察的动力学验证，以研究精氨酸代谢在 小儿T2D。我的中心假设是T2D儿童的精氨酸可用性不足（AIM 1）， 导致次优的β细胞功能，可以通过外源精氨酸施用来恢复（AIM 2）。如果我的话 被证明假设，补充精氨酸将在改善糖尿病预后起着至关重要的作用 在这个人群中，作为一种安全，低成本且随时可用的营养素。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对大量患者人群的机会 德克萨斯儿童医院和贝勒医学院的资源和强大的心态团队。通过 这个职业发展奖，我将使用A的最先进的动力学技术获得宝贵的经验 儿童以及生物统计学和数据分析中的稳定同位素示踪剂和靶向代谢组学。