Brain Ketone Metabolism in Type 1 Diabetes

NCT ID: NCT02471040

Last Updated: 2023-04-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 44 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-05-14
• Study Completion Date: 2022-04-04

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.

Conditions

Type 1 Diabetes; Hypoglycemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: SINGLE

Study Groups

Type 1 diabetic subjects

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.

Group Type: EXPERIMENTAL

Beta-hydroxybutyrate

Intervention Type: DRUG

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.

Normal Saline

Intervention Type: OTHER

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.

Healthy Subjects

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.

Group Type: ACTIVE_COMPARATOR

Beta-hydroxybutyrate

Intervention Type: DRUG

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.

Normal Saline

Intervention Type: OTHER

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.

Healthy Subjects CONTROL

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.

Group Type: ACTIVE_COMPARATOR

Normal Saline

Intervention Type: OTHER

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.

Interventions

Beta-hydroxybutyrate

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: DRUG

Normal Saline

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

Other Intervention Names

BHB; NaCl 0.9%

Eligibility Criteria

Inclusion Criteria

1. Type 1 diabetes mellitus of > 5 years (C-peptide negative, age 18-60 years, on intensive insulin therapy (HbA1c <7.5%)

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: collaborator

Yale University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Raimund Herzog, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

Yale New Haven Hospital

New Haven, Connecticut, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2R01DK101984-06

Identifier Type: NIH

Identifier Source: secondary_id

View Link

1208010648

Identifier Type: -

Identifier Source: org_study_id