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.

总结 1型糖尿病（T1 D）是一种无法治愈的衰弱性疾病。在最初的部分缓解后， 改善残余β细胞功能，“蜜月期”，不到17%的儿童达到血糖控制 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 早期死亡率。相反，严格的血糖控制-如通过更大的胰岛素剂量来匹配 碳水化合物消耗-也与并发症有关，即体重增加，胰岛素抵抗， 代谢综合征初步证据表明，一个非常低碳水化合物，高脂肪，（即，生酮饮食， KD）可能（1）通过减轻餐后血糖波动改善血糖控制，（2）减少 胰岛素暴露和对外周组织的相关副作用。患有T1 D的儿童可能 体验额外的好处，因为KD也可能（3）延长蜜月期-如病例报告所示- 通过对β细胞功能的免疫和/或代谢作用。具体地说，改善的胰岛素和胰岛素血症可能 促进β细胞静息，KD时β-羟基丁酸（βOHB）水平的生理学升高与 减少炎症和肠道微生物组的变化，这可能会减少β细胞自身免疫。 我们建议测试KD与标准饮食（SD）相比将延长糖尿病缓解并改善糖尿病患者的生活质量的假设。 糖尿病控制与儿童事件T1 D。在一项为期9个月的平行随机对照试验（RCT）中， 5-12岁的儿童（每组26人）将接受以家庭为基础的干预，包括提供食物和强化治疗。 营养和糖尿病教育，以促进KD vs SD。动态血糖监测（CGM）和蓝牙 启用的胰岛素笔将用于基于云的数据收集。人体测量学、空腹生物标志物和 将在基线时评估混合餐耐量试验后的受激C肽曲线下面积， 1、5和9个月。主要终点将是1至9个月之间刺激C肽的百分比变化。 次要终点将包括临床糖尿病缓解（胰岛素剂量调整后HbA 1c）的儿童百分比 [IADD 1c] <9）9个月时，来自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HDL胆固醇的比率）。探讨 我们还将评估肠道微生物组，代谢组， 免疫生物标志物对KD与SD的反应，并测试靶向生物标志物组与 β-细胞功能的变化和细胞凋亡。 与技术和药物治疗相比，饮食干预价格低廉，相对免费 主要副作用和直接翻译。KD可能对胰岛细胞功能、免疫功能和免疫功能有好处。 胰岛素血症，从而为患有T1 D的儿童提供了重大的治疗进展。无论 结果，我们的研究将填补一个重要的知识差距的安全性和有效性的KD儿童与 T1 D，尽管缺乏高质量的研究，但这种方法越来越受患者欢迎。