To determine the effect of re-activation of brain glucose metabolism induced by dichloroacetate (DCA) on cognitive function and counterregulatory hormone responses in patients with type 1 diabetes (T1DM) with recurrent hypoglycemia.

This will be a single center, placebo-controlled, cross-over, randomized clinical pilot study. The screening will take place at the Yale New Haven Hospital Research Unit (HRU) 10th floor, East Pavilion at 20 York St., New Haven, CT. At the screening visit informed consent will be obtained. Medical history and documents will be reviewed to screen potential subjects by inclusion and exclusion criteria. Subjects will receive a physical examination and laboratory blood work (BUN/creatinine, electrolytes, lipid profile, liver function, and HbA1c) as well as urine toxicology screens (to confirm self-report of alcohol, and drug information) to ensure good physical health.

Inclusion Criteria:

Group 1:

• Diagnosed C-peptide-negative T1DM, > 5 years duration, HbA1c of < 7.5%
• Intensive management, defined by frequent self-monitoring of glucose values and by the administration of 3 or more insulin injections each day (or the use of insulin pump therapy).
• History of severe hypoglycemia and hypoglycemia unawareness as assessed by the Guy's and Thomas' Minimally Modified Clarke Hypoglycemia Survey, the Gold Score and the Edinburgh Hypoglycemia Survey (see Appendix 1)
• Willingness to fast and to reduce insulin therapy for a limited time period

Group 2:

• Age, weight, and gender matched to group 1 subjects
• HbA1c <6%
• Good general health as evidenced by medical history and blood screening
• Willing to fast for a limited time period

Exclusion Criteria:

General criteria:

• Known allergic reactions to components of the study product(s)
• Participants carrying polymorphisms known to slow DCA metabolism (e.g. KGM or EGM allele [10])
• Treatment with another investigational drug or other intervention
• Active infection including hepatitis C, hepatitis B, HIV
• Any past or current history of alcohol or substance abuse
• Psychiatric or neurological disorders, including need for medications, including anxiolytics, and antidepressants
• Baseline Hgb < 10.5 g/dL in females, or < 12.5 g/dL in males. Blood donation within 30 days of the study
• History of coagulopathy or medical condition requiring long-term anticoagulant therapy (low-dose aspirin treatment is allowed)
• Co-existing cardiac, liver, and kidney disease
• Abnormal liver function tests
• GI disorders potentially interfering with the ability to absorb oral medications
• Women that are post-menopausal, pregnant (as assessed by pregnancy test that will be performed on female participants at reproductive age), or lactating.
• Any medical condition that, in the opinion of the investigators, will interfere with the safe completion of the study or study outcomes
• Any medication assumed less than 30 days before the study sessions that, in the opinion of the investigators, will interfere with the safe completion of the study or study outcomes.The list of medications to be avoided includes - but is not limited to - drugs known to influence metabolic and endocrine function (other than insulin in Group 1) and neuroactive medications.

Group 1:

• Detectable C-peptide;
• Untreated proliferative retinopathy;
• Creatinine ≥1.5 mg/dl, urinary albumin levels . 300 mg/day
• Autonomic neuropathy; painful peripheral neuropathy

Once stable hypoglycemia is reached, a cognitive testing battery will be administered by a study co-investigator who will be blinded to the treatment assignment.