Brain Ketone Metabolism in Type 1 Diabetes

Phase 1

Completed

• Conditions: Type 1 Diabetes; Hypoglycemia
• Interventions: Drug: Beta-hydroxybutyrate; Other: Normal Saline

• Registration Number: NCT02471040
• Lead Sponsor: Yale University

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.

Study Timeline

• Study Start: 2013-05-14
• Study First Submitted: 2015-05-28
• Study First Submitted QC: 2015-06-10
• Study First Posted: 2015-06-12
• Primary Completion: 2022-04-04
• Study Completion: 2022-04-04
• Status Verified: 2023-04
• Last Update Submitted: 2023-04-25
• Last Update Posted: 2023-04-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 44

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Type 1 diabetic subjects	Beta-hydroxybutyrate	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.
Type 1 diabetic subjects	Normal Saline	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 Subjects	Beta-hydroxybutyrate	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 Subjects	Normal Saline	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 Subjects CONTROL	Normal Saline	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.

Primary Outcome Measures

Name	Time	Method
Cognitive Function	Under clamped hypoglycemia (50 min from start)	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.

Trial Locations

Locations (1)

Yale New Haven Hospital; 🇺🇸 New Haven, Connecticut, United States