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Effects of Ketosis on Brain Function in Patients With T1DM

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ClinicalTrials.gov Identifier: NCT04219709
Recruitment Status : Recruiting
First Posted : January 7, 2020
Last Update Posted : January 7, 2020
Sponsor:
Collaborator:
Beth Israel Deaconess Medical Center
Information provided by (Responsible Party):
Belinda Lennerz, Boston Children’s Hospital

Brief 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. 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.

Condition or disease Intervention/treatment Phase
Type1diabetes Other: Very low carbohydrate diet Other: Standard carbohydrate diet Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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)
Primary Purpose: Supportive Care
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
Actual Study Start Date : January 3, 2020
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : June 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Very low carbohydrate diet
Dietary Intervention, food delivery
Other: Very low carbohydrate diet

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.


Active Comparator: Standard diet
Dietary Intervention, food delivery
Other: Standard carbohydrate diet

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.





Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Resting brain activation changes in brain areas related to cognition during hypoglycemia [ Time Frame: Diet week 5-12 ]
    Resting brain activation will be measured by arterial spin labeling (ASL) during euglycemia and hypoglycemia and differences will be reported

  2. Task-related brain activation changes during hypoglycemia in brain areas related to cognition [ Time Frame: Diet week 5-12 ]
    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

  3. Functional connectivity changes in brain areas related to cognition during hypoglycemia [ Time Frame: Diet week 5-12 ]
    Functional connectivity activation will be measured using resting state functional MRI during euglycemia and hypoglycemia and differences will be reported

  4. Response time changes during hypoglycemia [ Time Frame: Diet week 5-12 ]
    Response time to a working-memory cognitive task (n-back) will be measured during hypoglycemia and compared to the response time in euglycemia

  5. Cognitive performance during hypoglycemia [ Time Frame: Diet week 5-12 ]
    Response accuracy of a cognitive task (n-back) during hypoglycemia compared to euglycemia will be reported

  6. Hypoglycemia symptoms [ Time Frame: Diet week 5-12 ]
    A Hypoglycemia Symptoms Scale comprising 4 autonomic/neurogenic (sweating, palpitations, shaking, hunger) and 5 neuroglycopenic (drowsiness, confusion, difficulty concentrating, lightheadedness, and blurry vision) symptoms will be used to assess each symptom on a 0-10 visual analog scale (VAS) during euglycemia, hypoglycemia, and at the timepoint of participant report of hypoglycemic symptoms during the glycemic descent phase. Average scores for hypoglycemia symptoms overall, autonomic/neurogenic symptoms, and neuroglycopenic symptoms will be reported for each timepoint.

  7. Threshold for counter-regulatory hormone response [ Time Frame: Diet week 5-12 ]
    Levels of counter-regulatory hormone (epinephrine, glucagon, growth hormone, cortisol) will be measured every 10-15 minutes during the glycemic descent and hypoglycemic period and the blood glucose level at which a rise is first detected will be reported

  8. Levels of counter-regulatory hormones [ Time Frame: Diet week 5-12 ]
    Levels of counter-regulatory hormones (epinephrine, glucagon, growth hormone, cortisol) will be measured during at baseline, at the start and end of the euglycemic phase, and then every 10-15 minutes during glycemic descent and hypoglycemic period. Averages will be reported at each time point.

  9. Blood glucose level at which participant reports symptoms of hypoglycemia. [ Time Frame: Diet week 5-12 ]
    Participants will be instructed to push a response button when they first notice any symptoms of hypoglycemia during the glycemic descent phase.



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Ages Eligible for Study:   18 Years to 30 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males and females with T1D for at least 1 year
  • Age 18 to 30 years
  • Tanner stage ≥ IV
  • BMI 18.5-30 kg/m2
  • Stable glycemic control (HbA1c 7-9%)
  • Use of a continuous glucose monitor (CGM)
  • Use of an insulin pump
  • Attendance of at least 3 diabetes care visits over the past 12 months

Exclusion Criteria:

  • Ketoacidosis or severe hypoglycemia with seizure or coma in the past year
  • 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
  • Use of medications or supplements other than insulin to control blood glucose
  • 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 that could interfere with metabolic or glycemic variables
  • Significant psychiatric illness or use of psychotropic medication
  • Smoking, use of recreational drugs, or excessive alcohol consumption
  • Pregnancy or breastfeeding
  • Irregular menses
  • Anemia
  • Standard MRI exclusion criteria

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04219709


Contacts
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Contact: Svetlana Azova, MD 617-919-6675 svetlana.azova@childrens.harvard.edu
Contact: Belinda Lennerz, MD, PhD 857-218-3896 belinda.lennerz@childrens.harvard.edu

Locations
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United States, Massachusetts
Boston Children's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Svetlana C Azova, MD    617-919-6675 ext 6179196675    svetlana.azova@childrens.harvard.edu   
Contact: Belinda S Lennerz, MD PhD    8572183896    belinda.lennerz@childrens.harvard.edu   
Sponsors and Collaborators
Boston Children’s Hospital
Beth Israel Deaconess Medical Center
Investigators
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Principal Investigator: Belinda Lennerz, MD, PhD Boston Children’s Hospital

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Responsible Party: Belinda Lennerz, Instructor in Pediatric Endocrinology, Boston Children’s Hospital
ClinicalTrials.gov Identifier: NCT04219709    
Other Study ID Numbers: IRB-P00030039_2
First Posted: January 7, 2020    Key Record Dates
Last Update Posted: January 7, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Belinda Lennerz, Boston Children’s Hospital:
nutrition
very low carbohydrate diet
ketogenic diet
nutritional ketosis
cognitive function
brain
metabilism
ketones
ketosis
Additional relevant MeSH terms:
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Diabetes Mellitus, Type 1
Ketosis
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Acidosis
Acid-Base Imbalance