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Brain Ketone Metabolism in Type 1 Diabetes

Primary Purpose

Type 1 Diabetes, Hypoglycemia

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Beta-hydroxybutyrate
Normal Saline
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Type 1 Diabetes focused on measuring brain metabolism, cognitive function

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  1. Type 1 diabetes mellitus of > 5 years (C-peptide negative, age 18-60 years, on intensive insulin therapy (HbA1c <7.5%)
  2. Non-diabetic volunteers, age 18-65 years that do not meet any of the exclusion criteria.

Exclusion Criteria:

  1. Pregnancy
  2. Significant baseline anemia (hemoglobin <11.0 or hematocrit < 33%)
  3. A history of liver cirrhosis or porto-caval shunt surgery.
  4. Any contraindications for MRI scanning.
  5. Subjects that follow a vegetarian diet
  6. Subjects that exercise heavily on a regular basis (i.e. marathon runners, body builders or other forms of excessive exercise as determined by the PI)
  7. Subjects with a history of anxiety/ panic attacks

Sites / Locations

  • Yale New Haven Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

Active Comparator

Arm Label

Type 1 diabetic subjects

Healthy Subjects

Healthy Subjects CONTROL

Arm Description

Subjects will undergo a hyperinsulinemic-hypoglycemic clamp with a target glucose level of 55mg/dl. Once a stable glycemic state is reached, subjects will receive a bolus-continuous infusion beta-hydroxybutyrate (BHB) or infusion of a comparable volume of normal saline (placebo) to control for possible volume effects for the remainder of the study. Throughout the BHB or saline infusion cognitive function will be tested via a standardized testing battery.

Healthy control subjects will undergo a hyperinsulinemic-hypoglycemic clamp with a target glucose level of 55mg/dl. Once a stable glycemic state is reached, subjects will receive a bolus-continuous infusion beta-hydroxybutyrate (BHB) or infusion of a comparable volume of normal saline (placebo) to control for possible volume effects for the remainder of the study. Throughout the BHB or saline infusion cognitive function will be tested via a standardized testing battery.

Healthy control subjects will undergo a hyperinsulinemic-hypoglycemic clamp with a target glucose level of 55mg/dl. Once a stable glycemic state is reached, subjects will undergo an NMR test to characterize brain metabolism under hypoglycemia.

Outcomes

Primary Outcome Measures

Cognitive Function
Subjects from all groups will be studied using the NIH Toolbox Cognition Battery, which includes measurements of Executive Function, Attention, Episodic Memory, Language, Processing Speed and Working Memory.

Secondary Outcome Measures

Full Information

First Posted
May 28, 2015
Last Updated
April 25, 2023
Sponsor
Yale University
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT02471040
Brief Title
Brain Ketone Metabolism in Type 1 Diabetes
Official Title
Impact of Recurrent Hypoglycemia on Brain Ketone Metabolism in Type 1 Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Completed
Study Start Date
May 14, 2013 (Actual)
Primary Completion Date
April 4, 2022 (Actual)
Study Completion Date
April 4, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This study is designed to examine the value of infusing BHB in type 1 diabetic subjects during experimentally induced hypoglycemic episode in conjunction with testing of cognitive function. This will lay the basis for subsequent trials exploring the novel use of therapeutic doses of oral ketone formulations that are currently under commercial development, which could serve as adjunct therapies to protect the brain from hypoglycemia in type 1 diabetic subjects experiencing recurrent hypoglycemia.
Detailed Description
Healthy controls as well as type 1 diabetic subjects will undergo a hyperinsulinemic-hypoglycemic clamp with concomitant BHB or saline (control) infusion in random order. During each experimental condition the participants will complete a battery of validated cognitive tests that are sensitive to the cognitive impairment typically caused by hypoglycemia. An additional healthy control arm was added to the study design after the initial registration as a 2 arm study, to provide imaging results of normal healthy responses to hypoglycemia.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 1 Diabetes, Hypoglycemia
Keywords
brain metabolism, cognitive function

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Model Description
The added 3rd arm does not apply to the crossover design.
Masking
Participant
Allocation
Randomized
Enrollment
44 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Type 1 diabetic subjects
Arm Type
Experimental
Arm Description
Subjects will undergo a hyperinsulinemic-hypoglycemic clamp with a target glucose level of 55mg/dl. Once a stable glycemic state is reached, subjects will receive a bolus-continuous infusion beta-hydroxybutyrate (BHB) or infusion of a comparable volume of normal saline (placebo) to control for possible volume effects for the remainder of the study. Throughout the BHB or saline infusion cognitive function will be tested via a standardized testing battery.
Arm Title
Healthy Subjects
Arm Type
Active Comparator
Arm Description
Healthy control subjects will undergo a hyperinsulinemic-hypoglycemic clamp with a target glucose level of 55mg/dl. Once a stable glycemic state is reached, subjects will receive a bolus-continuous infusion beta-hydroxybutyrate (BHB) or infusion of a comparable volume of normal saline (placebo) to control for possible volume effects for the remainder of the study. Throughout the BHB or saline infusion cognitive function will be tested via a standardized testing battery.
Arm Title
Healthy Subjects CONTROL
Arm Type
Active Comparator
Arm Description
Healthy control subjects will undergo a hyperinsulinemic-hypoglycemic clamp with a target glucose level of 55mg/dl. Once a stable glycemic state is reached, subjects will undergo an NMR test to characterize brain metabolism under hypoglycemia.
Intervention Type
Drug
Intervention Name(s)
Beta-hydroxybutyrate
Other Intervention Name(s)
BHB
Intervention Description
Both healthy subjects and type 1 diabetic subjects will receive a bolus-continuous infusion of 40umol/min/kg of BHB for 5 min, followed by a 12µmol/min/kg of BHB or infusion of a comparable volume of normal saline (placebo) to control for possible volume effects for the remainder of the study.
Intervention Type
Other
Intervention Name(s)
Normal Saline
Other Intervention Name(s)
NaCl 0.9%
Intervention Description
Both healthy subjects and type 1 diabetic subjects will receive a bolus-continuous infusion of 40umol/min/kg of BHB for 5 min, followed by a 12µmol/min/kg of BHB or infusion of a comparable volume of normal saline (placebo) to control for possible volume effects for the remainder of the study.
Primary Outcome Measure Information:
Title
Cognitive Function
Description
Subjects from all groups will be studied using the NIH Toolbox Cognition Battery, which includes measurements of Executive Function, Attention, Episodic Memory, Language, Processing Speed and Working Memory.
Time Frame
Under clamped hypoglycemia (50 min from start)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Type 1 diabetes mellitus of > 5 years (C-peptide negative, age 18-60 years, on intensive insulin therapy (HbA1c <7.5%) Non-diabetic volunteers, age 18-65 years that do not meet any of the exclusion criteria. Exclusion Criteria: Pregnancy Significant baseline anemia (hemoglobin <11.0 or hematocrit < 33%) A history of liver cirrhosis or porto-caval shunt surgery. Any contraindications for MRI scanning. Subjects that follow a vegetarian diet Subjects that exercise heavily on a regular basis (i.e. marathon runners, body builders or other forms of excessive exercise as determined by the PI) Subjects with a history of anxiety/ panic attacks
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Raimund Herzog, MD
Organizational Affiliation
Yale School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale New Haven Hospital
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States

12. IPD Sharing Statement

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Brain Ketone Metabolism in Type 1 Diabetes

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