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

膳食碳水化合物对新诊断糖尿病儿童的糖尿病控制和 β 细胞功能的影响。

• 批准号: 10637032
• 负责人: BELINDA S LENNERZ
• 金额: $ 81.18万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637032
• 关键词: Adult; Adverse effects; American; Appearance; Area Under Curve; Autoimmunity; Bacteroides; Beta Cell; Bifidobacterium; Biological Markers; Blood Circulation; Blood Glucose; Bluetooth; Body Weight; Body mass index; C-Peptide; C-reactive protein; Carbohydrates; Case Study; Cell physiology; Child; Childhood diabetes; Clinical; Clinical Trials; Complication; Consumption; Continuous Glucose Monitor; Data Collection; Diabetes Mellitus; Diagnosis; Diet; Dietary Carbohydrates; Dietary Intervention; Disease; Disease remission; Dose; Family; Fasting; Fatty acid glycerol esters; Food; Glucose; Glycemic Index; Glycosylated hemoglobin A; Health; High Density Lipoprotein Cholesterol; IL17 gene; Immune; Immunologic Markers; Inflammasome; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interleukin-1 beta; Interleukin-10; Interleukin-6; Interphase Cell; Intervention; Knowledge; Link; Metabolic; Metabolic Marker; Metabolic syndrome; Microbe; Newly Diagnosed; Outcome; Partial Remission; Pathway interactions; Patients; Peripheral; Pharmacological Treatment; Physiological; Physiology; Production; Randomized, Controlled Trials; Recommendation; Research; Residual state; Risk; Safety; Selection Bias; TNF gene; Technology; Testing; Therapeutic; Time; Tissues; Triglycerides; Variant; Weight Gain; aged; arm; beta-Hydroxybutyrate; blood glucose regulation; burden of illness; cloud based; diabetes control; diabetes education; experience; glucose disposal; glycemic control; gut microbes; gut microbiome; improved; indexing; inflammatory marker; insulin sensitivity; interleukin-23; ketogenic diet; ketogentic; metabolome; microbial; microbial composition; mortality; multidisciplinary; multiple omics; nutrition; nutrition education; obesogenic; pharmacologic; primary endpoint; response biomarker; secondary endpoint; side effect; targeted biomarker; uptake

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.

概括 第一型糖尿病（T1D）是一种令人衰弱的疾病，无法治愈。最初的部分缓解后 改善残留β细胞功能，“蜜月期”，少于17％的儿童达到了血糖 美国糖尿病协会（ADA）推荐的目标，使数百万美元处于并发症的风险 和早期死亡率。相反，紧密的血糖控制 - 以更大的胰岛素剂量达到以匹配 消耗的碳水化合物 - 还与并发症，即体重增强，胰岛素抵抗和 代谢综合征。初步证据表明，高碳水化合物高脂（即生酮饮食， KD）在T1d 5月（1）通过缓解餐后血糖偏移和（2）减少血糖控制 胰岛素暴露和对周围组织的不利影响。发生事件T1d的儿童五月 体验额外的好处，因为KD也可能（3）延长蜜月期 - 如在案例报告中所见 - 通过免疫和/或代谢对β细胞功能的影响。具体而言，改善的血糖和胰岛素血症可能 在KD上促进β细胞休息，并在KD上进行物理升高 减少炎症和肠道微生物组的变化，可能会降低ß细胞自身免疫性。 我们建议检验以下假设：KD与标准饮食（SD）将延长糖尿病的缓解并改善 糖尿病患者的糖尿病控制T1D。在9个月的平行随机对照试验（RCT）中，52 5-12岁的儿童（每只手臂26岁）将接受基于家庭的干预措施，以食品分娩和密集 营养和糖尿病教育以促进KD vs SD。连续葡萄糖监测（CGM）和蓝牙 启用的胰岛素笔将用于基于云的数据收集。人类测量法，禁食生物标志物和 在基线时，将评估曲线下曲线下刺激的C肽面积， 1、5和9个月。主要终点将是1到9个月之间刺激的C肽的变化百分比。 次要终点将包括临床糖尿病缓解儿童的百分比（胰岛素剂量调整后的HBA1C [IADD1C] <9）在9个月时，连续葡萄糖监测的血糖控制指标和标记 代谢健康（BMI，胰岛素抵抗指数以及甘油三酸酯与HDL胆固醇的比率）。探索 与改善的ß细胞功能有关的途径，我们还将评估肠道微生物组，代谢组和 免疫学生物标志物对KD与SD的反应以及针对性生物标记组与 β细胞功能和血糖的变化。 与技术和药物治疗相比，饮食干预价格便宜，相对免费 主要副作用，直接翻译。 KD可能会对ß细胞功能，血糖和 胰岛素血症，从而为患有T1D的儿童提供了重大的治疗进步。不管 结果，我们的研究将缩小有关KD对患有KD的安全性和效率的重要知识差距 T1D，一种增加患者受欢迎程度目的地缺乏高质量研究的方法。