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.

We propose to examine whether a ketogenic compared to a standard diet in children with newly diagnosed diabetes would extend the honeymoon period – a transient improvement in insulin production that occurs shortly after diagnosis and greatly improves diabetes control and disease burden. Despite major pharmacological and technological advances, diabetes control remains poor in most children with diabetes, while conversely tighter diabetes control has been associated with weight gain, placing millions at risk for complications. A ketogenic diet could have benefits on insulin production, diabetes control and body weight, would be directly translatable, inexpensive and relatively free of major side-effects.