Effect of Dietary Carbohydrate on Diabetes Control and Beta Cell Function in Children with Newly Diagnosed Diabetes.”

摘要 1型糖尿病(T1D)是一种无法治愈的衰弱疾病。在最初的部分缓解后， 残存β细胞功能改善，“蜜月期”，不到17%的儿童达到血糖 美国糖尿病协会(ADA)推荐的目标，使数百万人面临并发症的风险 和早期死亡率。相反，严格的血糖控制--通过更大剂量的胰岛素来实现 摄入碳水化合物-也与并发症有关，即体重增加、胰岛素抵抗和 代谢综合征。初步证据表明，非常低碳水化合物、高脂肪(即生酮饮食， Kd)可以(1)通过减轻餐后血糖漂移来改善血糖控制，以及(2)减少 胰岛素暴露及其对周围组织的相关不良反应。患有T1D事件的儿童可能会 体验额外的好处，因为KD还可以(3)延长蜜月期--如案例报告所示- 通过免疫和/或代谢对β细胞功能的影响。具体地说，改善血糖和胰岛素血症可能 促进β细胞休息，与KD上生理性升高的β-羟丁酸(βOHb)水平有关 以减少炎症和肠道微生物群的变化，这可能会降低？细胞自身免疫力。 我们建议对KD与标准饮食(SD)将延长糖尿病缓解和改善的假设进行检验。 发生T1D事件的儿童的糖尿病控制。在一项为期9个月的平行随机对照试验(RCT)中，52 5-12岁的儿童(每臂26人)将接受以家庭为基础的食品运送和强化干预 营养和糖尿病教育，促进一场KD VS SD。连续血糖监测(CGM)和蓝牙技术 启用的胰岛素笔将用于基于云的数据收集。人体测量学、空腹生物标志物和 混合餐耐量试验后曲线下的刺激C肽面积将在基线时进行评估， 1、5和9个月。主要终点将是在1至9个月内刺激的C肽的百分比变化。 次要终点将包括临床糖尿病缓解(胰岛素剂量调整HbA1c)的儿童百分比 9)9个月时，连续血糖监测的血糖控制指数，以及 代谢健康(BMI、胰岛素抵抗指数和甘油三酯与高密度脂蛋白的比率)。去探索 我们还将评估肠道微生物组、代谢组和 KD与SD的免疫生物标记物反应及靶向生物标记物与 β细胞功能和血糖的变化。 与技术和药物治疗相比，饮食干预成本低，相对免费 主要副作用，并可直接翻译。KD可能对？细胞功能、血糖和 治疗胰岛素血症，从而为患有T1D的儿童提供重大的治疗进展。不管 结果，我们的研究将弥合关于KD治疗儿童的安全性和有效性的重要知识差距 尽管缺乏高质量的研究，T1D仍是一种越来越受患者欢迎的方法。

SUMMARY Type one diabetes mellitus (T1D) is a debilitating disease with no cure. After an initial partial remission with improved residual β-cell function, the “honeymoon period”, less than 17% of children achieve the glycemic targets recommended by the American Diabetes Association (ADA), placing millions at risk for complications and early mortality. Conversely, tight glycemic control - as achieved with greater insulin doses to match carbohydrates consumed - has also been linked to complications, namely weight-gain, insulin resistance, and metabolic syndrome. Preliminary evidence suggests that a very low-carbohydrate, high-fat, (i.e., ketogenic diet, KD) in T1D may (1) improve glycemic control by mitigating postprandial glycemic excursions and (2) reduce insulin exposure and associated adverse effects on peripheral tissues. Children with incident T1D may experience additional benefits, as a KD may also (3) prolong the honeymoon period - as seen in case reports - via immune and/or metabolic effects on β-cell function. Specifically, improved glycemia and insulinemia may promote β-cell rest, and the physiologically elevated β-hydroxybutyrate (βOHB) levels on a KD have been linked to decreased inflammation and gut microbiome changes that may reduce ß-cell autoimmunity. We propose to test the hypothesis that a KD vs. standard diet (SD) will prolong diabetes remission and improve diabetes control in children with incident T1D. In a 9-months parallel randomized controlled trial (RCT), fifty-two children (26 per arm) aged 5-12 years will receive a family-based intervention with food deliveries and intensive nutrition and diabetes education to promote a KD vs SD. Continuous glucose monitoring (CGM) and Bluetooth enabled insulin pens will be used for cloud-based data collection. Anthropometrics, fasting biomarkers and stimulated C-peptide area under the curve following a mixed meal tolerance test will will be assessed at baseline, 1, 5 and 9 months. The primary endpoint will be percent change in stimulated C-peptide between 1 and 9 months. Secondary endpoints will include percent children with clinical diabetes remission (insulin dose adjusted HbA1c [IADD1c] <9) at 9 months, indices of glycemic control from continuous glucose monitoring, and markers of metabolic health (BMI, indices of insulin resistance, and the ratio of triglycerides to HDL cholesterol). To explore pathways related to improved ß-cell function, we will also evaluate gut microbiome, metabolome, and immunologic biomarker responses to a KD vs SD and test interactions of targeted biomarker groups with changes in β-cell function and glycemia. Compared with technological and pharmacological treatments, dietary intervention is inexpensive, relatively free of major side-effects and directly translatable. A KD may have benefits on ß-cell function, glycemia and insulinemia, and would thereby provide a major therapeutic advance for children living with T1D. Regardless of outcome, our research will close an important knowledge gap on the safety and efficacy of a KD for children with T1D, an approach with increasing patient popularity despite lack of high-quality research.