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

项目摘要/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(T1D)患者的肾病：1，2尚未达到接近正常血糖水平 T1D患者发生严重低血糖的风险增加3倍。目前，还没有具体的饮食习惯 美国糖尿病协会对儿科T1D的建议；3然而，越来越多的 患有T1D的青少年和他们的父母对极低碳水化合物饮食改善血糖感兴趣 Control.4 人们一直在犹豫是否给青少年开出这样的饮食处方，因为还没有严格的研究 在这个年龄段表演。 这项建议的目标是确定非常低的安全性和有效性 T1D青少年的碳水化合物饮食：观察代谢和神经系统的变化 这种节食法。这项建议的目标1使用随机交叉研究设计来比较 当患有T1D的青少年遵循标准或非常低时，使用连续血糖监测仪的目标范围 碳水化合物饮食。在高血糖和低血糖范围内的时间较短，表明安全性更好。这个 糖尿病酮症酸中毒和严重低血糖的发作次数也将被报告。目标2将 用两步法比较两种饮食对低血糖的反调节激素反应 高胰岛素正血糖-低血糖钳夹技术。 将使用稳定的同位素输注来评估 肝脏葡萄糖生成率(从肝脏释放葡萄糖)和 脂肪中的甘油代谢 组织。此外，非常低的碳水化合物饮食可能会导致血液中更高的酮水平(营养 酮症)，但关于这将如何影响对低血糖和其他神经系统的认识，人们知之甚少 改变。AIM 3将使用有效问卷评估低血糖症状的变化 低血糖部分 夹闭，这将与fMRI的表现相关联。 通过这个目标，我们将 确定在极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。 纳利博士组建了一个拥有多种技能的领导团队来指导她进行这项研究。纳利医生的 首席导师威廉·坦博兰博士在儿科T1D研究方面拥有超过45年的经验，并 指导了耶鲁大学14名现任内科科学家教职员工。Raimund Herzog博士(共同导师)具有以下方面的专业知识 低血糖和酮症对大脑的代谢影响，并将指导Nally博士在以下方面的研究 学习。在儿科T1D、持续血糖监测和高胰岛素正血糖方面拥有专业知识- 降血糖钳，詹妮弗·谢尔博士(共同导师)将确保Nally博士拥有必要的技能来进行 在此提出的研究。Nally博士将在复杂的血糖和脂肪测量方面获得专业知识 使用同位素示踪剂和胰岛素钳技术的代谢，以及功能磁共振成像解释的技能，以及 完成生物统计学方面的课程，推进她成为一名独立调查员的目标。

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.