Brain Ketone Metabolism in Type 1 Diabetes

NCT02471040 | Completed Phase 1

• 2 other identifiers: 12080106482R01DK101984-06
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

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.

Conditions

Type 1 Diabetes; Hypoglycemia

Keywords

brain metabolism; cognitive function

Outcome Measures

Primary Outcomes (1)

• 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.

  Under clamped hypoglycemia (50 min from start)

Study Arms (3)

Type 1 diabetic subjects

EXPERIMENTAL

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.

Drug: Beta-hydroxybutyrate; Other: Normal Saline

Healthy Subjects

ACTIVE COMPARATOR

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.

Drug: Beta-hydroxybutyrate; Other: Normal Saline

Healthy Subjects CONTROL

ACTIVE COMPARATOR

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.

Other: Normal Saline

Interventions

Beta-hydroxybutyrate 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.

Also known as: BHB

Healthy Subjects; Type 1 diabetic subjects

Normal Saline 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.

Also known as: NaCl 0.9%

Healthy Subjects; Healthy Subjects CONTROL; Type 1 diabetic subjects

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• Yale University: lead
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): collaborator

Study Sites (1)

Yale New Haven Hospital

New Haven, Connecticut, 06510, United States

Location

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Hypoglycemia

Interventions

3-Hydroxybutyric Acid; Saline Solution; Sodium Chloride

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Hydroxybutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Ketone Bodies; Ketones; Fatty Acids, Volatile; Fatty Acids; Lipids; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Raimund Herzog, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: DIAGNOSTIC
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The added 3rd arm does not apply to the crossover design.

Study Record Dates

• First Submitted: May 28, 2015
• First Posted: June 12, 2015
• Study Start: May 14, 2013
• Primary Completion: April 4, 2022
• Study Completion: April 4, 2022
• Last Updated: April 27, 2023

Record last verified: 2023-04

Locations

US (1)