Brain Ketone Metabolism in Type 1 Diabetes

Yale University

Status and phase: Completed; Phase 1

Conditions: Hypoglycemia; Type 1 Diabetes

Treatments: Drug: Beta-hydroxybutyrate; Other: Normal Saline

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT02471040

2R01DK101984-06 (U.S. NIH Grant/Contract)

1208010648

Details and patient eligibility

About

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.

Full 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.

Enrollment: 44 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts 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

Trial design

Primary purpose: Diagnostic

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Single Blind

---

44 participants in 3 patient groups

Type 1 diabetic subjects

Experimental group

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.

Treatment:

Other: Normal Saline

Drug: Beta-hydroxybutyrate

Healthy Subjects

Active Comparator group

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.

Treatment:

Other: Normal Saline

Drug: Beta-hydroxybutyrate

Healthy Subjects CONTROL

Active Comparator group

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.

Treatment:

Other: Normal Saline