Type1diabetesNCT04219709
Effects of Ketosis on Brain Function in Patients With T1DM
A study testing Very low carbohydrate diet and Standard carbohydrate diet in people with Type1diabetes, run by Boston Children's Hospital at 1 site in United States.
Trial summary
The scientific goal of this study is to examine the effects of a ketogenic diet on hypoglycemia tolerance and brain function in people with type 1 diabetes mellitus (T1D) and to clarify the mechanistic role of ketones in this process. Read more about this study
- Who is it for?
- Ages 18 to 40 years
- Conditions the study is for
- Type1diabetes
- What is being tested?
- Very low carbohydrate diet and Standard carbohydrate diet
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUnited States
- Study dates
- 3 Jan 2020to 31 Jul 2026
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Males and females with T1D for at least 1 year
- Age 18 to 40 years
- Tanner stage ≥ IV
- BMI 18.5-35 kg/m2
- Stable glycemic control (HbA1c 6.5-9%)
- Use of a continuous glucose monitor (CGM)
- Use of an insulin pump
- Attendance of at least 1 diabetes care visit over the past 12 months (including virtual)
Who cannot join
- Ketoacidosis or severe hypoglycemia with seizure or coma in the past 6 months
- Dietary restrictions or intolerances that are incompatible with the planned food deliveries, e.g. celiac disease, gastroparesis, certain food allergies
- Following a weight-loss or otherwise restrictive diet
- Vigorous exercise >2 hours on >3 days a week
- History of an eating disorder or at risk for eating disorder, assessed by the Eating Disorders Diagnostic Scale (EDDS)
- Major medical illness or use of medications other than insulin and metformin that could interfere with metabolic or glycemic variables
Show all 14Show fewer
- Significant psychiatric illness
- Smoking, use of recreational drugs, or excessive alcohol consumption
- Pregnancy or breastfeeding
- Anemia
- For participants who undergo MRI:
- Standard MRI exclusion criteria
- Irregular menses
- Use of psychotropic medication other than SSRIs or other mild antidepressant or anxiety medications (unless these medications are safe to be held for several days to allow for the acquisition of MRI data).
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Boston Childrens Hospital
Boston, Massachusetts, 02115
About this study
Official title: Brain Function, Cognition, and Hypoglycemia Tolerance in Patients With Type 1 Diabetes Mellitus in the Setting of Nutritional Ketosis Versus Standard Carbohydrate Diet
The scientific goal of this study is to examine the effects of a ketogenic diet on hypoglycemia tolerance and brain function in people with type 1 diabetes mellitus (T1D) and to clarify the mechanistic role of ketones in this process. Glycemic management of T1D is typified by alternating periods of hyper- and hypo-glycemia. Because brain metabolism under usual conditions depends on glucose, acute hypoglycemia leads to immediate complications including impaired cognitive function and a counter-regulatory hormone response. Recurrent hypoglycemia is associated with functional and structural changes in the brain and contributes to the cognitive decline observed in individuals with diabetes. The state of nutritional ketosis (as it occurs during fasting or when following a ketogenic [very low carbohydrate] diet) may protect against these acute and chronic complications. As the body relies on fat metabolism, ketone bodies build up and provide an alternative fuel for the brain. Studies during hypoglycemia have shown better cognitive function and less hypoglycemia symptoms in the setting of nutritional ketosis or with ketone administration. This physiological benefit may have special relevance for people with T1D who experience hypoglycemia frequently. To date, no mechanistic studies have examined brain effects of nutritional ketosis in T1D; nor have any trials explored the potential relevance of this for diabetes care.
Read the detailed description
To test the hypothesis that a ketogenic diet increases hypoglycemia tolerance and improves brain function and cognitive performance during hypoglycemia, the researchers propose a randomized mechanistic study using insulin infusions and neuroimaging. The study will leverage an existing randomized controlled trial (RCT) in 32 young adults with T1D who will receive a ketogenic vs a standard carbohydrate diet for 12 weeks. Researchers will conduct a euglycemic-hypoglycemic insulin clamp using a continuous infusion of insulin, along with a glucose infusion that is adjusted to keep blood glucose levels normal (90 mg/dL), followed by a slow drop to hypoglycemia (50 mg/dL). Researchers will assess activation and connectivity of relevant brain areas by magnetic resonance imaging (MRI). Using continuous imaging during the gradual glycemic descent from 90 mg/dL to 50 mg/dL, the researchers will establish the glycemic threshold at which the hypothalamus becomes activated. Using a combination of MRI modalities, they will assess brain activation and connectivity changes during hypoglycemia versus euglycemia, both during rest and in relation to a cognitive task. Brain findings will be integrated with physiologic (blood levels of glucose, ketones, free fatty acids, counter-regulatory hormones) and behavioral (reaction time, cognitive task performance, hypoglycemia symptoms scale) parameters. In additional studies, researchers will give an oral ketone drink to raise blood ketone levels in participants in the standard carbohydrate diet arm. They will perform the same insulin infusion and MRI investigations to clarify the mechanistic role of ketones in mediating brain activation patterns. Comparison will be between nutritional vs no ketosis, exogenous vs no ketosis, and nutritional vs exogenous ketosis.
- Conditions
- Type1diabetes
- Being tested
- Very low carbohydrate diet, Standard carbohydrate diet
- Keywords
- nutrition, very low carbohydrate diet, ketogenic diet, nutritional ketosis, cognitive function, brain, metabolism, ketones, ketosis
- Medical subject headings
- Ketosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Very low carbohydrate dietOther
All meals will be delivered and participants will consume study foods exclusively. Participants will receive a fiber supplement with each meal as needed to promote digestive health, and a daily multi-vitamin, magnesium and omega-3 supplement to ascertain micronutrient sufficiency. Participants will be weighed at each study visit and the diet plan will be adjusted for satiety and weight-maintenance.
The diet composition will be as follows: 5% carbohydrate, 75% fat, 20% protein.
Standard carbohydrate dietOther
All meals will be delivered and participants will consume study foods exclusively. Participants will receive a daily multi-vitamin and omega-3 supplement to ascertain micronutrient sufficiency. Participants will be weighed at each study visit and the diet plan will be adjusted for satiety and weight-maintenance.
The diet composition will be as follows: 50% carbohydrate, 30% fat, 20% protein.
| Study group | Role | What they receive |
|---|---|---|
| Very low carbohydrate diet | Experimental | Dietary Intervention, food delivery Receives: Other: Very low carbohydrate diet |
| Standard diet | Active comparator | Dietary Intervention, food delivery Receives: Other: Standard carbohydrate diet |
What is being measured
The primary outcome is the main question the study is designed to answer.
Glycemic threshold for hypothalamic activation
The blood glucose level at which hypothalamic activation is detected by continuous BOLD functional MRI during a 40 min glycemic descent from 90 to 50 mg/dL
Measured: Diet week 5-12
Secondary outcomes (7)
Resting brain activation changes in brain areas related to cognition during hypoglycemia
Resting brain activation will be measured by arterial spin labeling (ASL) during euglycemia and hypoglycemia and differences will be reported
Measured: Diet week 5-12
Task-related brain activation changes during hypoglycemia in brain areas related to cognition
Task-related brain activation will be measured during a working memory task (n-back) by BOLD during euglycemia and hypoglycemia and differences will be reported
Measured: Diet week 5-12
Functional connectivity changes in brain areas related to cognition during hypoglycemia
Functional connectivity activation will be measured using resting state functional MRI during euglycemia and hypoglycemia and differences will be reported
Measured: Diet week 5-12
Response time changes during hypoglycemia
Response time to a working-memory cognitive task (n-back) will be measured during hypoglycemia and compared to the response time in euglycemia
Measured: Diet week 5-12
Cognitive performance during hypoglycemia
Response accuracy of a cognitive task (n-back) during hypoglycemia compared to euglycemia will be reported
Measured: Diet week 5-12
Hypoglycemia symptoms
A Hypoglycemia Symptoms Scale comprising 6 autonomic/neurogenic (sweating, palpitations, trembling, weakness, nausea, and hunger) and 5 neuroglycopenic (drowsiness, confusion, difficulty concentrating, lightheadedness, and headache) symptoms will be used to assess each symptom on a 0-4 scale (higher scores indicate more symptoms) during euglycemia and hypoglycemia. Average scores for hypoglycemia symptoms overall, autonomic/neurogenic symptoms, and neuroglycopenic symptoms will be reported for each time point.
Measured: Diet week 5-12
Blood glucose level at which participant reports symptoms of hypoglycemia.
Participants will be instructed to push a response button when they first notice any symptoms of hypoglycemia during the glycemic descent phase.
Measured: Diet week 5-12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Jan 2020
- Study start3 Jan 2020
- Primary completion31 Jul 2026 (estimated)
- Study completion31 Jul 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Type1diabetesStudies of the same condition, open and under way.
- More trials run by Boston Children's HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Participants will be randomized in a parallel design to receive a standard carbohydrate diet versus very low carbohydrate diet. Both of diet groups will undergo euglycemic-hypoglycemic insulin clamps and MRI studies to assess brain hypoglycemia tolerance. The standard diet group will undergo an additional euglycemic-hypoglycemic insulin clamp - with and without exogenous oral ketones in random order.
- Masking
- None (open label)
- Enrolment
- 24 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Boston Children's Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Beth Israel Deaconess Medical Center
- Responsible party
- Principal investigator, Belinda Lennerz, Boston Children's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04219709
- Sponsor's protocol ID
- IRB-P00030039_2
- Status last verified
- Dec 2024
- First submitted
- 3 Jan 2020
- Last updated
- 18 Dec 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Brain Function, Cognition, and Hypoglycemia Tolerance in Patients With Type 1 Diabetes Mellitus in the Setting of Nutritional Ketosis Versus Standard Carbohydrate Diet
- ClinicalTrials.gov ID
- NCT04219709
- Acronym / sponsor ID
- IRB-P00030039_2
- Conditions
- Type1diabetes
- Keywords
- nutrition, very low carbohydrate diet, ketogenic diet, nutritional ketosis, cognitive function, brain, metabolism, ketones
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 24 participants (estimated)
- Lead sponsor
- Boston Children's HospitalUniversity, hospital or other
- Collaborators
- Beth Israel Deaconess Medical Center
- Study start
- 3 Jan 2020 (actual)
- Primary completion
- 31 Jul 2026 (estimated)
- Study completion
- 31 Jul 2026 (estimated)
- First posted
- 7 Jan 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The scientific goal of this study is to examine the effects of a ketogenic diet on hypoglycemia tolerance and brain function in people with type 1 diabetes mellitus (T1D) and to clarify the mechanistic role of ketones in this process. Glycemic management of T1D is typified by alternating periods of hyper- and hypo-glycemia. Because brain metabolism under usual conditions depends on glucose, acute hypoglycemia leads to immediate complications including impaired cognitive function and a counter-regulatory hormone response. Recurrent hypoglycemia is associated with functional and structural changes in the brain and contributes to the cognitive decline observed in individuals with diabetes. The state of nutritional ketosis (as it occurs during fasting or when following a ketogenic [very low carbohydrate] diet) may protect against these acute and chronic complications. As the body relies on fat metabolism, ketone bodies build up and provide an alternative fuel for the brain. Studies during hypoglycemia have shown better cognitive function and less hypoglycemia symptoms in the setting of nutritional ketosis or with ketone administration. This physiological benefit may have special relevance for people with T1D who experience hypoglycemia frequently. To date, no mechanistic studies have examined brain effects of nutritional ketosis in T1D; nor have any trials explored the potential relevance of this for diabetes care.
Detailed description
To test the hypothesis that a ketogenic diet increases hypoglycemia tolerance and improves brain function and cognitive performance during hypoglycemia, the researchers propose a randomized mechanistic study using insulin infusions and neuroimaging. The study will leverage an existing randomized controlled trial (RCT) in 32 young adults with T1D who will receive a ketogenic vs a standard carbohydrate diet for 12 weeks. Researchers will conduct a euglycemic-hypoglycemic insulin clamp using a continuous infusion of insulin, along with a glucose infusion that is adjusted to keep blood glucose levels normal (90 mg/dL), followed by a slow drop to hypoglycemia (50 mg/dL). Researchers will assess activation and connectivity of relevant brain areas by magnetic resonance imaging (MRI). Using continuous imaging during the gradual glycemic descent from 90 mg/dL to 50 mg/dL, the researchers will establish the glycemic threshold at which the hypothalamus becomes activated. Using a combination of MRI modalities, they will assess brain activation and connectivity changes during hypoglycemia versus euglycemia, both during rest and in relation to a cognitive task. Brain findings will be integrated with physiologic (blood levels of glucose, ketones, free fatty acids, counter-regulatory hormones) and behavioral (reaction time, cognitive task performance, hypoglycemia symptoms scale) parameters. In additional studies, researchers will give an oral ketone drink to raise blood ketone levels in participants in the standard carbohydrate diet arm. They will perform the same insulin infusion and MRI investigations to clarify the mechanistic role of ketones in mediating brain activation patterns. Comparison will be between nutritional vs no ketosis, exogenous vs no ketosis, and nutritional vs exogenous ketosis.
Study design
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Participants will be randomized in a parallel design to receive a standard carbohydrate diet versus very low carbohydrate diet. Both of diet groups will undergo euglycemic-hypoglycemic insulin clamps and MRI studies to assess brain hypoglycemia tolerance. The standard diet group will undergo an additional euglycemic-hypoglycemic insulin clamp - with and without exogenous oral ketones in random order.
| Arm | Type | Receives |
|---|---|---|
| Very low carbohydrate diet | Experimental | Other: Very low carbohydrate dietDietary Intervention, food delivery |
| Standard diet | Active comparator | Other: Standard carbohydrate dietDietary Intervention, food delivery |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- Males and females with T1D for at least 1 year
- Age 18 to 40 years
- Tanner stage ≥ IV
- BMI 18.5-35 kg/m2
- Stable glycemic control (HbA1c 6.5-9%)
Key exclusion criteria (14 listed)
- Ketoacidosis or severe hypoglycemia with seizure or coma in the past 6 months
- Dietary restrictions or intolerances that are incompatible with the planned food deliveries, e.g. celiac disease, gastroparesis, certain food allergies
- Following a weight-loss or otherwise restrictive diet
- Vigorous exercise >2 hours on >3 days a week
- History of an eating disorder or at risk for eating disorder, assessed by the Eating Disorders Diagnostic Scale (EDDS)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Very low carbohydrate dietAll meals will be delivered and participants will consume study foods exclusively. Participants will receive a fiber supplement with each meal as needed to promote digestive health, and a daily multi-vitamin, magnesium and omega-3 supplement to ascertain micronutrient sufficiency. Participants will be weighed at each study visit and the diet plan will be adjusted for satiety and weight-maintenance. The diet composition will be as follows: 5% carbohydrate, 75% fat, 20% protein. | Other | Very low carbohydrate diet |
| Standard carbohydrate dietAll meals will be delivered and participants will consume study foods exclusively. Participants will receive a daily multi-vitamin and omega-3 supplement to ascertain micronutrient sufficiency. Participants will be weighed at each study visit and the diet plan will be adjusted for satiety and weight-maintenance. The diet composition will be as follows: 50% carbohydrate, 30% fat, 20% protein. | Other | Standard diet |
Primary outcome
Glycemic threshold for hypothalamic activation
Time frame: Diet week 5-12
The blood glucose level at which hypothalamic activation is detected by continuous BOLD functional MRI during a 40 min glycemic descent from 90 to 50 mg/dL
7 secondary outcomes
Resting brain activation changes in brain areas related to cognition during hypoglycemia
Time frame: Diet week 5-12
Task-related brain activation changes during hypoglycemia in brain areas related to cognition
Time frame: Diet week 5-12
Functional connectivity changes in brain areas related to cognition during hypoglycemia
Time frame: Diet week 5-12
Response time changes during hypoglycemia
Time frame: Diet week 5-12
Cognitive performance during hypoglycemia
Time frame: Diet week 5-12
Hypoglycemia symptoms
Time frame: Diet week 5-12
Blood glucose level at which participant reports symptoms of hypoglycemia.
Time frame: Diet week 5-12
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Dec 2024.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Very low carbohydrate diet and Standard carbohydrate diet in people with Type1diabetes, run by Boston Children's Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 18 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Belinda Lennerz, MD PhD (+1 617 355 7476, belinda.lennerz@childrens.harvard.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Glycemic threshold for hypothalamic activation (time frame: Diet week 5-12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Dec 2024; AzTrials last refreshed its copy on 6 Nov 2026.