Metabolic and Neurological Changes Induced by a Very Low Carbohydrate Diet in Youth with Type 1 Diabetes

项目概要/摘要 来自两项里程碑式试验（DCCT/EDIC）的30年随访数据表明，强化胰岛素 达到接近正常血糖水平的管理可降低视网膜病变、神经病变和 1型糖尿病（T1 D）患者的肾病。1，2然而， 使T1 D患者发生严重低血糖的风险增加3倍。目前，没有具体的饮食 美国糖尿病协会对儿童T1 D的建议;3然而，越来越多的 患有T1 D的青少年及其父母对极低碳水化合物饮食感兴趣，以改善血糖 控制。4 由于没有严格的研究，因此对青少年开这种饮食处方一直犹豫不决。 在这个年龄段的表现。 本提案的目的是确定极低剂量的 通过观察T1 D青少年的代谢和神经系统变化， 这种饮食。本提案的目的1使用随机交叉研究设计，比较 当T1 D青少年遵循标准与非常低时，使用动态血糖监测仪的目标范围 碳水化合物饮食处于高血糖和低血糖范围的时间越短，安全性越好。的 还将报告糖尿病酮症酸中毒和重度低血糖的发作次数。目标2将 使用两步比较两种饮食对低血糖的反调节激素反应 高胰岛素血症正常血糖-低血糖钳夹技术。 稳定同位素输注将用于评估 肝脏葡萄糖生成速率（肝脏葡萄糖释放）， 脂肪甘油代谢 组织.此外，非常低的碳水化合物饮食可能导致血液中较高的酮水平（营养不良）。 酮症），但很少有人知道这将如何影响低血糖和其他神经系统的意识 变化目标3将使用经验证的问卷评估低血糖症状的变化， 低血糖部分 钳，这将与功能磁共振成像的结果。 通过这一目标，我们将 确定在非常低碳水化合物饮食中发生的酮症是否会减弱低血糖的警告信号。 博士Nally组建了一个具有多种技能的领导团队来指导她进行这项研究。Nally医生 主要导师William Tamborlane博士在儿科T1 D研究方面拥有超过45年的经验， 指导耶鲁大学14名现任医生科学家教师。Raimund Herzog博士（共同导师）在以下方面拥有专业知识： 低血糖和酮症对大脑的代谢影响，并将指导Nally博士这些方面的研究。 study.凭借在儿科T1 D、动态血糖监测和高胰岛素血症血糖正常方面的专业知识， Jennifer Sherr博士（共同导师）将确保Nally博士具有进行低血糖钳操作所需的技能 在此提出的研究。纳利博士将获得葡萄糖和脂肪的复杂措施的专业知识 使用同位素示踪剂和胰岛素钳夹技术的代谢，以及功能磁共振成像解释的技能， 完成生物统计学课程，推进她成为独立调查员的目标。

PROJECT SUMMARY/ABSTRACT Thirty years of follow up data from two landmark trials (DCCT/EDIC) demonstrates that intensive insulin management to achieve near-normal blood glucose levels decreases the risk of retinopathy, neuropathy, and nephropathy for individuals with type 1 diabetes (T1D).1,2 Yet, achieving near-normal blood glucose levels increases the risk of severe hypoglycemia in those with T1D by 3-fold. Currently, there are no specific dietary recommendations from the American Diabetes Association for pediatric T1D;3 however, a growing number of youth with T1D and their parents are interested in very low carbohydrate diets to improve blood glucose control.4 There has been hesitance to prescribe such diets to adolescents as no rigorous studies have been performed in this age group. The goal of this proposal is to determine the safety and efficacy of a very low carbohydrate diet in adolescents with T1D by looking at metabolic and neurological changes that occur with this diet. Aim 1 of this proposal uses a randomized crossover study design to compare the time spent in the target range using continuous glucose monitors when adolescents with T1D follow a standard versus very low carbohydrate diet. Less time in the hyperglycemic and hypoglycemic ranges indicates better safety. The number of episodes of diabetic ketoacidosis and severe hypoglycemia will also be reported. Aim 2 will compare the counterregulatory hormone response to hypoglycemia between the 2 diets using the 2-step hyperinsulinemic euglycemic-hypoglycemic clamp technique. Stable isotope infusions will be used to assess rates of hepatic glucose production (glucose release from the liver) and glycerol metabolism from adipose tissue. Further, very low carbohydrate diets are likely to cause higher ketone levels in the blood (nutritional ketosis), but there is little known about how this will affect awareness of hypoglycemia and other neurological changes. Aim 3 will assess changes in symptoms of hypoglycemia using validated questionnaires during the hypoglycemia portion of the clamp, which will be correlated with fMRI findings. Through this aim, we will determine if the ketosis that develops in very low carbohydrate diets will blunt warning signs of hypoglycemia. Dr. Nally has assembled a leadership team with a diverse skillset to guide her in this research. Dr. Nally's primary mentor, Dr. William Tamborlane, has over 45 years of experience in pediatric T1D research and has mentored 14 current physician scientist faculty at Yale. Dr. Raimund Herzog (co-mentor) has expertise in the metabolic effects of hypoglycemia and ketosis on the brain and will guide Dr. Nally with these aspects of the study. With expertise in pediatric T1D, continuous glucose monitoring and the hyperinsulinemic euglycemic- hypoglycemic clamps, Dr. Jennifer Sherr (co-mentor) will ensure Dr. Nally has the skillset necessary to conduct the studies proposed herein. Dr. Nally will gain expertise in sophisticated measures of glucose and fat metabolism using isotope tracers and insulin clamp techniques, as well as skills in fMRI interpretation, and complete coursework in biostatistics, advancing her goal to become an independent investigator.