Carbohydrate Beta Cell Function and Glucose Control in Children With Diabetes
Study Details
Study Description
Brief Summary
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:
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Does a ketogenic diet prolong the honeymoon period of type 1 diabetes?
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Does a ketogenic diet improve diabetes control?
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Is a ketogenic diet safe, acceptable and sustainable in children with newly diagnosed diabetes?
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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.
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Diabetes care devices will be connected for cloud-based data collection.
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Bi-weekly data downloads and remote check-ins will assess dietary intake, satisfaction with diet and study procedures, and possible safety concerns.
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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.
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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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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N/A |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: ketogenic diet 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
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.
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| Active Comparator: standard diet 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
Groceries will be delivered and participants will receive education on nutrition, meal preparation, and diabetes care strategies. Participants will consume study-prescribed foods exclusively.
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Outcome Measures
Primary Outcome Measures
- Decline in Beta-cell Function [Change between 1 and 9 months]
Percent change in C-peptide 2-h area under the curve after a mixed-meal tolerance test (ΔCP%).
Secondary Outcome Measures
- Time in Range (TIR) 70-180 mg/dl [Over 9 months and at 21 months]
From continuous glucose monitoring (CGM) - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.
- Longitudinal Change in Beta-cell Function [0, 1, 5, and 21 months]
C-peptide 2-h area under the curve after a mixed-meal tolerance test.
- Duration of Clinical Diabetes Remission [1, 5, 9, and 21 months]
Calculated based on percent children with insulin dose corrected HbA1c (IDAA1c) <9.
- Time in Range (TIR) <70 mg/dl [Over 9 months and at 21 months]
From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.
- Time in Range (TIR) <55 mg/dl [Over 9 months and at 21 months]
From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.
- Time in Range (TIR) >180 mg/dl [Over 9 months and at 21 months]
From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation 2-week increments.
- Time in Range (TIR) >250 mg/dl [Over 9 months and at 21 months]
From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.
- Average Blood Glucose [Over 9 months and at 21 months]
From CGM - will be computed throughout study participation in 2-week increments.
- Coefficient of Glycemic Variation (CV) [Over 9 months and at 21 months]
From CGM - will be computed by dividing glucose standard deviation by glucose average throughout study participation in 2-week increments.
- Mean Amplitude of Glycemic Excursions (MAGE) [Over 9 months and at 21 months]
From CGM - will be computed using published formula throughout study participation in 2-week increments.
- Total Daily Insulin Dose [Over 9 months and at 21 months]
From insulin administration device uploads - will be computed in units per kg throughout study participation in 2-week increments.
- HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) [1, 5, 9, and 21 months]
Calculated from fasting blood draw [fasting insulin (µU/ml) × fasting plasma glucose (mg/dl)]/405.
- BMI [1, 5, 9, and 21 months]
Weight divided by height squared.
- Lipid panel [1, 5, 9, and 21 months]
Fasting blood - total, LDL and HDL cholesterol, and triglycerides.
- HDL to Triglyceride Ratio [1, 5, 9, and 21 months]
Fasting blood
- Lipoprotein Subfractions [1, 5, 9, and 21 months]
Fasting blood
- Inflammasome, targeted [1, 5, 9, and 21 months]
Interleukins 1β, 17, 23, 6, 10; high sensitivity c-reactive protein; tumor necrosis factor α, interferon gamma
- Microbiome, targeted and untargeted [1, 5, 9, and 21 months]
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.
- Metabolome, targeted and untargeted [1, 5, 9, and 21 months]
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.
- Problem Areas in Diabetes (PAID) - child [1, 3, 5, 7, 9, and 21 months]
Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate greater burden.
- Problem Areas in Diabetes (PAID) - parent [1, 3, 5, 7, 9, and 21 months]
Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate greater burden.
- Pediatric Quality of Life (PEDSQL) General Module - parent [1, 3, 5, 7, 9, and 21 months]
Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate better quality of life.
- Pediatric Quality of Life (PEDSQL) General Module - child [1, 3, 5, 7, 9, and 21 months]
Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate better quality of life.
- Pediatric Quality of Life (PEDSQL) Diabetes Module - parent [1, 3, 5, 7, 9, and 21 months]
Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate less problems.
- Pediatric Quality of Life (PEDSQL) Diabetes Module - child [1, 3, 5, 7, 9, and 21 months]
Validated questionnaire, scored according to published standards. Scores range 0-100, higher scores indicate less problems.
- Child Eating Disorder Examination Questionnaire (ChEDE-Q8) [1, 3, 5, 7, 9, and 21 months]
Validated questionnaire, scored according to published standards. Scores range 0-42, higher scores are worse.
- WE-CARE (WEll-being and Satisfaction of CAREgivers of Children with Diabetes) [1, 3, 5, 7, 9, and 21 months]
Validated questionnaire, scored according to published standards.
- Perceptions on Diet Management of Diabetes [1, 3, 5, 7, 9, and 21 months]
Questionnaire to assess participants' and caregivers' perceptions of the influence of the diet on their diabetes management.
- Qualitative patient perspectives, interview - parent [1, 9 and 21 months]
Interviews will be held with children and caregivers separately after implementation and completion of the intervention.
- Qualitative patient perspectives, interview - child [1, 9 and 21 months]
Focus groups and interviews will be held with children and caregivers separately after implementation and completion of the intervention.
- Qualitative patient perspectives, focus group - parent [2-9 months]
Focus groups will be held with children and caregivers separately once during the study.
- Qualitative patient perspectives, focus group - child [2-9 months]
Focus groups will be held with children and caregivers separately once during the study.
Other Outcome Measures
- Time in Range (TIR) 70-140 mg/dl [Over 9 months and at 21 months]
From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.
- Time in Range (TIR) >140 mg/dl [Over 9 months and at 21 months]
From CGM - percent time spent in the specified glycemic target range will be computed throughout study participation in 2-week increments.
- BOHB (beta-hydroxybutyrate), fasting blood concentration [Over 9 months and at 21 months]
Obtained at weekly increasing to monthly intervals as effect modifier of beta-cell function.
- Growth [1, 5, 9, and 21 months]
Safety Measure - Height standard deviation score will be calculated from serial height measurements obtained during study visits using CDC age and sex specific references.
- Growth velocity [1, 5, 9, and 21 months]
Safety Measure - Growth velocity will be calculated from serial height measurements obtained during study visits.
- Weigh-gain [1, 5, 9, 21 months]
Safety Measure - Weight SDS and gain will be calculated from serial weight measures obtained during study visits with calibrated scale.
- Confirmed Ketoacidosis [Over 9 months]
Safety Measure - Defined by elevated BOHB, blood pH <7.3 and serum bicarbonate <15. Rates will be computed as total number of events divided by total patient years of follow-up.
- Severe Hypoglycemia [Over 9 months]
Safety Measure - Defined as blood glucose < 55 mg/dl and requiring glucagon or resulting in seizure or coma. Rates will be computed as total number of events divided by total patient years of follow-up.
- Diabetes Related Emergency Visits [Over 9 months]
Safety Measure - Rates will be computed as total number of events divided by total patient years of follow-up.
- Diabetes Related Hospitalizations [Over 9 months]
Safety Measure - Rates will be computed as total number of events divided by total patient years of follow-up.
- Study termination for disordered eating [Over 9 months]
Safety Measure - Eat-26 score > 20 with clinical confirmation. Total number of events.
- Study termination for growth deceleration [Over 9 months]
Safety Measure - Undesired weight loss or significant deceleration in longitudinal growth may warrant termination of study participation. Total number of events will be computed.
- Study termination for dyslipidemia [Over 9 months]
Safety Measure - LDL >200 mg/dl will trigger review of additional risk factors and may prompt diet modification to lower intake of saturated fats. If persistent, study participation may be terminated. Total number of events will be computed.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Children aged 5 to 12 years.
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Within one month of diabetes diagnosis.
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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]).
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Family committed and able to participate in study education and implement dietary intervention.
Exclusion Criteria:
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Dietary needs incompatible with the study meal plans, (e.g., vegan, major food intolerances/allergies).
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Eating disorders as assessed by Eat-26 Eating Attitudes Test.
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Major medical illness or use of medications other than insulin that could interfere with metabolic or glycemic variables.
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Major psychiatric illness.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Boston Children's Hospital
- University of South Florida
- Indiana University
Investigators
- Principal Investigator: Belinda Lennerz, Boston Children's Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
- Lennerz BS, Barton A, Bernstein RK, Dikeman RD, Diulus C, Hallberg S, Rhodes ET, Ebbeling CB, Westman EC, Yancy WS Jr, Ludwig DS. Management of Type 1 Diabetes With a Very Low-Carbohydrate Diet. Pediatrics. 2018 Jun;141(6):e20173349. doi: 10.1542/peds.2017-3349. Epub 2018 May 7.
- Lennerz BS, Koutnik AP, Azova S, Wolfsdorf JI, Ludwig DS. Carbohydrate restriction for diabetes: rediscovering centuries-old wisdom. J Clin Invest. 2021 Jan 4;131(1):e142246. doi: 10.1172/JCI142246.
- IRB-P00044330