Effects of Ketosis on Brain Function in Patients With T1DM

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.

Study Overview

• Status: Recruiting
• Conditions: Type1diabetes
• Intervention / Treatment: Other: Very low carbohydrate diet; Other: Standard carbohydrate diet

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 Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Svetlana Azova, MD; Phone Number: 617-919-6675; Email: svetlana.azova@childrens.harvard.edu
• Study Contact Backup: Name: Belinda Lennerz, MD, PhD; Phone Number: 857-218-3896; Email: belinda.lennerz@childrens.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Recruiting
      • Boston Children's Hospital
      • Contact: Svetlana Azova, MD; Phone Number: 6179196675 617-919-6675; Email: svetlana.azova@childrens.harvard.edu
      • Contact: Belinda S Lennerz, MD, PhD; Phone Number: 8572183896; Email: belinda.lennerz@childrens.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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)

Exclusion Criteria:

• 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
• Significant psychiatric illness
• Smoking, use of recreational drugs, or excessive alcohol consumption
• Pregnancy or breastfeeding
• Anemia

• For participants who undergo MRI:

  1. Standard MRI exclusion criteria
  2. Irregular menses
  3. 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Diet week 5-12

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Boston Children's Hospital
• Collaborators: Beth Israel Deaconess Medical Center
• Investigators: Principal Investigator: Belinda Lennerz, MD, PhD, Boston Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2020
• Primary Completion (Estimated): July 31, 2024
• Study Completion (Estimated): July 31, 2024

Study Registration Dates

• First Submitted: January 3, 2020
• First Submitted That Met QC Criteria: January 3, 2020
• First Posted (Actual): January 7, 2020

Study Record Updates

• Last Update Posted (Actual): July 3, 2023
• Last Update Submitted That Met QC Criteria: June 29, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: cognitive function; nutrition; brain; ketogenic diet; metabolism; ketones; very low carbohydrate diet; nutritional ketosis; ketosis
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Acid-Base Imbalance; Acidosis; Diabetes Mellitus, Type 1; Ketosis
• Other Study ID Numbers: IRB-P00030039_2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No