Regulation of Brain Glucose Metabolism in Type 1 Diabetes

Study Overview
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Brief Summary
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This is a prospective randomized placebo-controlled double-blind crossover study determining the effect of dichloroacetate on brain glucose metabolism under clamped hypoglycemia in T1DM.

Detailed Description
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This study is a prospective randomized placebo-controlled double-blind crossover study designed to address the hypothesis that dichloroacetate has the ability to re-activate brain glucose metabolism under clamped hypoglycemia. The study population is comprised of intensively treated persons with T1D with frequent exposure to hypoglycemia, who have cognitive deficits under hypoglycemia that could be attributed to changes in brain glucose oxidation. The investigators will test the experimental compound DCA in a mechanistic study that determines whether brain metabolism is restored by this intervention, or whether the drug effect was primarily caused by changes in physiology outside of the brain.

Official Title
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Regulation of Brain Glucose Metabolism in Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1, Hypoglycemia Unawareness

Intervention / Treatment
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* Drug: Dichloroacetate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: T1DM subjects with: a history of severe hypoglycemia and/or hypoglycemia unawareness or a history of severe hypoglycemia with a blood glucose <54 mg/dL, requiring the assistance of another person (with recovery after the administration of oral carbohydrate, intravenous glucose, or glucagon) or at least 2 values <54mg/dl during 2 weeks of CGMS testing during the week prior to study. Exclusion Criteria: Age < 18 years or >55 years. Body weight >85 kg at screening visit BMI > 30 (female) and >30 (male) kg/m2. Untreated proliferative retinopathy carriers of glutathione transferase Z1 (GSTZ-1) gene polymorphisms that predispose to DCA accumulation and toxicity

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>capsule with excipient only, no active drug. | Drug: Dichloroacetate<br>* Dichloroacetate has a long safety record of administration to humans with a rare metabolic disorder for over 40 years. It has been given orally to patients with T2DM for up to a week without any problems and other laboratory or significant clinical adverse effects were not noted. It activates mitochondrial PDH flux, a key regulator of glucose oxidation.<br>* Other names: DCA;|
| Active Comparator: Dichloroacetate<br>sodium salt of dichloroacetate, 1000mg | Drug: Dichloroacetate<br>* Dichloroacetate has a long safety record of administration to humans with a rare metabolic disorder for over 40 years. It has been given orally to patients with T2DM for up to a week without any problems and other laboratory or significant clinical adverse effects were not noted. It activates mitochondrial PDH flux, a key regulator of glucose oxidation.<br>* Other names: DCA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PDH flux in the frontal lobe | Neuronal PDH flux in the frontal lobe measured by DMI of labeled glucose | 1 day |