Carbohydrate Beta Cell Function and Glucose Control in Children With Diabetes

Study Overview
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Brief Summary
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The goal of this clinical trial is to test the effects of a ketogenic diet on the progression and control of type 1 diabetes in children with newly diagnosed diabetes. The main questions to answer are: Does a ketogenic diet prolong the honeymoon period of type 1 diabetes? Does a ketogenic diet improve diabetes control? Is a ketogenic diet safe, acceptable and sustainable in children with newly diagnosed diabetes? What are the microbiome, inflammatory and metabolic changes linking diet to β-cell function? Participants will receive a combination of free meals, groceries, micronutrient supplements, and intensive diet and diabetes education for 9 months. Diabetes care devices will be connected for cloud-based data collection. Bi-weekly data downloads and remote check-ins will assess dietary intake, satisfaction with diet and study procedures, and possible safety concerns. During five study visits held at at baseline, 1, 5, 9 and 21 months, an intravenous catheter (IV) will be placed for collection of 5 blood samples before and up to 2 hours after a liquid test meal (protein shake) to assess insulin response. A stool sample will also be collected to assess microbiome changes. Children and their caregivers will participate in focus groups, semi-structured interviews, and online questionnaires to assess their experience with the diet and diabetes care, general well-being and quality of life. Comparison will be made between a ketogenic vs standard diet.

Detailed Description
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Type I diabetes is caused by an autoimmune destruction of insulin producing β-cells in the pancreas, resulting in absolute insulin deficiency. In the first months after diagnosis, a small number of β-cells typically remain and, by producing insulin, significantly improve diabetes control and reduce disease burden. Preliminary data suggest that this early disease stage entitled the honeymoon period might be extended by a ketogenic diet, which would provide a major therapeutic advantage and may reduce chronic disease burden. To test the hypothesis that a ketogenic vs. standard diet will extend the honeymoon period and improve diabetes control in children, the researchers are conducting a study employing education and food deliveries of a ketogenic or standard diet to children and their families. Fifty-two children aged 5 to 12 years with newly diagnosed diabetes will participate. Children will be assigned by chance (randomized) to receive either a ketogenic or a standard diet for 9 months. Chances to be assigned to either diet are 50:50 like a coin flip, and 26 children will participate in each diet arm. Participants will receive a combination of free meals, groceries, micronutrient supplements, and intensive diet and diabetes education throughout the 9 months. Continuous glucose monitoring (CGM) and Bluetooth enabled insulin pens will be used for cloud-based data collection. Bi-weekly data downloads and remote check-ins will be performed to assess dietary intake, satisfaction with diet and study procedures, and possible safety concerns. Participants are instructed to measure blood ketone levels with their home ketone meter anytime blood glucose levels exceed a safety threshold and to call the study physician for persistent low glucose levels or ketones above diet specific safety thresholds. Study visits are held at at baseline, 1, 5, 9 and 21 months to collect height, weight, stool and blood samples for hormones, metabolites and inflammatory biomarkers. At each visit, an intravenous catheter (IV) will be placed to collect fasting blood samples, followed by a liquid test meal (protein shake) and collection of four additional blood samples from the IV over the course of two hours. Prior to each visit, participants will collect stool samples at home using provided kits. In addition, participants and their families will participate in focus groups, semi-structured interviews, and online questionnaires to asses their food intake, experience with the diet, diabetes care burden and complications, and general well-being and quality of life.

Official Title
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Effect of Dietary Carbohydrate on Diabetes Control and Beta Cell Function in Children With Newly Diagnosed Diabetes

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Other: Ketogenic diet, food delivery and education
* Other: Standard diet, food delivery and education


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children aged 5 to 12 years. Within one month of diabetes diagnosis. Type 1 diabetes confirmed by immediate insulin requirement with autoimmunity markers (≥2 positive antibodies [glutamate decarboxylase-65, islet-antigen-2, zinc transporter-8, insulin [prior to first insulin dose]). Family committed and able to participate in study education and implement dietary intervention. Exclusion Criteria: Dietary needs incompatible with the study meal plans, (e.g., vegan, major food intolerances/allergies). Eating disorders as assessed by Eat-26 Eating Attitudes Test. Major medical illness or use of medications other than insulin that could interfere with metabolic or glycemic variables. Major psychiatric illness.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ketogenic diet<br>The diet will be high in protein and healthy fats and comprise meat, fish, fibrous vegetables, nuts, dairy, and berries. Macronutrient composition will be   5% carbohydrate, 20% protein, 70% fat. Participants will receive a daily multi-vitamin, magnesium supplement, and supplemental salt (bouillon cubes) to ascertain micronutrient sufficiency and help with transition to the diet. | Other: Ketogenic diet, food delivery and education<br>* Meals and groceries will be delivered and participants will receive education on nutrition, meal preparation, and diabetes care strategies. Participants will consume study-prescribed foods exclusively.<br>|
| Active Comparator: standard diet<br>The diet will be consistent with prevailing dietary guidelines and recommendations and contain meat, fish, grains, vegetables, fruit and dairy. At least 50% of grain-based products will be whole grains. Meats will be primarily lean, and dairy products will be fat-free or low-fat. Macronutrient composition will be  50% carbohydrate (<10% added sugars), 20% protein, 30% fat. Participants will receive a daily multi-vitamin supplement to ascertain micronutrient sufficiency. | Other: Standard diet, food delivery and education<br>* Groceries will be delivered and participants will receive education on nutrition, meal preparation, and diabetes care strategies. Participants will consume study-prescribed foods exclusively.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Decline in Beta-cell Function | Percent change in C-peptide 2-h area under the curve after a mixed-meal tolerance test (ΔCP%). | Change between 1 and 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time in Range (TIR) 70-180 mg/dl | From continuous glucose monitoring (CGM) - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments. | Over 9 months and at 21 months | 
| Longitudinal Change in Beta-cell Function | C-peptide 2-h area under the curve after a mixed-meal tolerance test. | 0, 1, 5, and 21 months | 
| Duration of Clinical Diabetes Remission | Calculated based on percent children with insulin dose corrected HbA1c (IDAA1c) <9. | 1, 5, 9, and 21 months | 
| Time in Range (TIR) <70 mg/dl | From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments. | Over 9 months and at 21 months | 
| Time in Range (TIR) <55 mg/dl | From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments. | Over 9 months and at 21 months | 
| Time in Range (TIR) >180 mg/dl | From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation 2-week increments. | Over 9 months and at 21 months | 
| Time in Range (TIR) >250 mg/dl | From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments. | Over 9 months and at 21 months | 
| Average Blood Glucose | From CGM - will be computed throughout study participation in 2-week increments. | Over 9 months and at 21 months | 
| Coefficient of Glycemic Variation (CV) | From CGM - will be computed by dividing glucose standard deviation by glucose average throughout study participation in 2-week increments. | Over 9 months and at 21 months | 
| Mean Amplitude of Glycemic Excursions (MAGE) | From CGM - will be computed using published formula throughout study participation in 2-week increments. | Over 9 months and at 21 months | 
| Total Daily Insulin Dose | From insulin administration device uploads - will be computed in units per kg throughout study participation in 2-week increments. | Over 9 months and at 21 months | 
| HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) | Calculated from fasting blood draw [fasting insulin (µU/ml) × fasting plasma glucose (mg/dl)]/405. | 1, 5, 9, and 21 months | 
| BMI | Weight divided by height squared. | 1, 5, 9, and 21 months | 
| Lipid panel | Fasting blood - total, LDL and HDL cholesterol, and triglycerides. | 1, 5, 9, and 21 months | 
| HDL to Triglyceride Ratio | Fasting blood | 1, 5, 9, and 21 months | 
| Lipoprotein Subfractions | Fasting blood | 1, 5, 9, and 21 months | 
| Inflammasome, targeted | Interleukins 1β, 17, 23, 6, 10; high sensitivity c-reactive protein; tumor necrosis factor α, interferon gamma | 1, 5, 9, and 21 months | 
| Microbiome, targeted and untargeted | Extraction and sequencing will be performed by Qiagen PowerSoil DNA extraction using Qiagen's DNeasy 96 PowerSoil Pro QIAcube HT Kit (480), followed by whole genome sequencing (WGS) using a miniaturized version of the NEBNext Ultra FS II method. | 1, 5, 9, and 21 months | 
| Metabolome, targeted and untargeted | Blood samples will be processed using liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR). The LC-MS analyses will be carried out on a Sciex triple quadrupole mass spectrometer couple to an Exion ultra-performance LC system. The targeted analysis will utilize the Biocrates Q500 targeted metabolomics assay which quantifies more than 500 metabolites over 26 chemical classes (Biocrates Inc., Innsbruck, Austria). Data processing to yield metabolite concentrations in micromolar units will utilize the Biocrates MetIDQ software. The NMR data will be acquired on a Bruker Avance NEO 700 MHz NMR equipped with a TCI cryoprobe and a SampleXPress automatic sample changer. The data will be processed using the Chenomx NMR Processor and Profiler packages (Chenomx, Edmonton, CA) to yield quantitative data in millimolar units. | 1, 5, 9, and 21 months | 
| Problem Areas in Diabetes (PAID) - child | Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate greater burden. | 1, 3, 5, 7, 9, and 21 months | 
| Problem Areas in Diabetes (PAID) - parent | Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate greater burden. | 1, 3, 5, 7, 9, and 21 months | 
| Pediatric Quality of Life (PEDSQL) General Module - parent | Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate better quality of life. | 1, 3, 5, 7, 9, and 21 months | 
| Pediatric Quality of Life (PEDSQL) General Module - child | Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate better quality of life. | 1, 3, 5, 7, 9, and 21 months | 
| Pediatric Quality of Life (PEDSQL) Diabetes Module - parent | Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate less problems. | 1, 3, 5, 7, 9, and 21 months | 
| Pediatric Quality of Life (PEDSQL) Diabetes Module - child | Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate less problems. | 1, 3, 5, 7, 9, and 21 months | 
| Child Eating Disorder Examination Questionnaire (ChEDE-Q8) | Validated questionnaire, scored according to published standards. Scores range 0-42, higher scores are worse. | 1, 3, 5, 7, 9, and 21 months | 
| WE-CARE (WEll-being and Satisfaction of CAREgivers of Children with Diabetes) | Validated questionnaire, scored according to published standards. | 1, 3, 5, 7, 9, and 21 months | 
| Perceptions on Diet Management of Diabetes | Questionnaire to assess participants' and caregivers' perceptions of the influence of the diet on their diabetes management. | 1, 3, 5, 7, 9, and 21 months | 
| Qualitative patient perspectives, interview - parent | Interviews will be held with children and caregivers separately after implementation and completion of the intervention. | 1, 9 and 21 months | 
| Qualitative patient perspectives, interview - child | Focus groups and interviews will be held with children and caregivers separately after implementation and completion of the intervention. | 1, 9 and 21 months | 
| Qualitative patient perspectives, focus group - parent | Focus groups will be held with children and caregivers separately once during the study. | 2-9 months | 
| Qualitative patient perspectives, focus group - child | Focus groups will be held with children and caregivers separately once during the study. | 2-9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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carbohydrate reduced, low-carb, diabetes, keto