Effects of Ketosis on Brain Function in Patients With T1DM

NCT ID: NCT04219709

Last Updated: 2024-12-18

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 24 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-01-03
• Study Completion Date: 2026-07-31

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.

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

Keywords

nutrition; very low carbohydrate diet; ketogenic diet; nutritional ketosis; cognitive function; brain; metabolism; ketones; ketosis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: NONE

Study Groups

Very low carbohydrate diet

Dietary Intervention, food delivery

Group Type: EXPERIMENTAL

Very low carbohydrate diet

Intervention Type: OTHER

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 diet

Dietary Intervention, food delivery

Group Type: ACTIVE_COMPARATOR

Standard carbohydrate diet

Intervention Type: OTHER

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: OTHER

Eligibility Criteria

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:

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).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Beth Israel Deaconess Medical Center

OTHER

Sponsor Role: collaborator

Boston Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Belinda Lennerz

Instructor in Pediatric Endocrinology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Boston Childrens Hospital

Boston, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Belinda Lennerz, MD PhD

Role: CONTACT

Phone: +1 617 355 7476

Email: belinda.lennerz@childrens.harvard.edu

Other Identifiers

IRB-P00030039_2

Identifier Type: -

Identifier Source: org_study_id