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

基本信息

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
项目类别：
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

项目摘要

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/摘要在儿童肥胖流行的同时，儿童 2 型糖尿病 (T2D) 正在成为一个重要的公众问题最近的数据显示，在过去十年中，儿童 T2D 的发病率增加了 50%。 T2D 占新诊断儿童糖尿病病例的四分之一。患有 T2D 的儿童具有侵袭性。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该疾病的特点是胰岛素抵抗和胰岛素分泌受损。 T2D 的分子基础尚未完全阐明本研究旨在揭示精氨酸的作用。小儿T2D发病机制中的代谢及外源性精氨酸对β细胞的影响精氨酸是一种已知的胰腺 β 细胞胰岛素分泌兴奋剂。 (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 独立机制，通过刺激鸟苷酸环化酶、膜去极化和代谢精氨酸对胰腺 β 细胞的作用取决于细胞的可用精氨酸。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”精氨酸的可用性及其各种途径的相对贡献对成人 T2D 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而发生在 T2D 人群的一个子集中，即患有 T2D 的人群。酮症倾向糖尿病（KPD），我们的小组发现患有酮症倾向的糖尿病（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减少。此外，它们的胰岛素分泌也显着减少。在我对 2 型糖尿病 (T2D) 儿童的初步数据中，我发现服用精氨酸后反应恢复了。他们的代谢特征与患有 KPD 的成人相似。具体来说，患有 T2D 的儿童的禁食率较低。在本提案中，我将寻求精氨酸、瓜氨酸（精氨酸前体）和谷氨酰胺（瓜氨酸前体）的水平。对这些假设产生的观察结果进行动力学验证，以研究精氨酸代谢在我的中心假设是患有 T2D 的儿童精氨酸可用性不足（目标 1），导致 β 细胞功能不佳，可通过给予外源精氨酸来恢复（目标 2）。假设已得到证实，精氨酸补充剂将在改善糖尿病结局方面发挥临床重要作用在这个人群中，作为一种安全、低成本、容易获得的营养素，我非常适合进行这项研究。鉴于我之前的临床和研究经验，以及我接触大量患者群体的机会，我获得了丰富的经验德克萨斯儿童医院和贝勒医学院的资源和强大的指导团队。通过这个职业发展奖，我将获得使用最先进的动力学技术的宝贵经验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。