Vitamin E Supplementation in Hyperinsulinism/Hyperammonemia Syndrome

Congenital hyperinsulinism (HI) is a rare disorder of pancreatic beta cell insulin secretion
that causes persistent and severe hypoglycemia starting at birth.
Hyperinsulinism/hyperammonemia (HI/HA) syndrome is the second most common type of congenital
HI and is caused by activating mutations in glutamate dehydrogenase (GDH). Patients with
HI/HA exhibit fasting hyperinsulinemic hypoglycemia, protein-induced hypoglycemia,
hyperammonemia, seizures, and intellectual disability independent of hypoglycemia. These
effects result from abnormal GDH activity in the beta cells, liver and kidney cells, neurons,
and astrocytes. The only available treatment for HI/HA syndrome is diazoxide, which acts on
the beta cells to decrease insulin secretion but has no effect on GDH activity itself or on
other cell types. Thus, there remains a significant unmet need for improved therapies for
this disorder. Preliminary data show that Vitamin E (alpha-tocopherol) inhibits GDH activity
in cell lines and improves hypoglycemia in a GDH HI mouse model. Based on these preclinical
studies, Investigators hypothesize that Vitamin E will inhibit GDH activity and may impact
hyperinsulinemic hypoglycemia and hyperammonemia in subjects with HI/HA syndrome. This
hypothesis will be tested in a future study. In this initial pilot study, investigators will
assess the tolerability of oral Vitamin E supplementation in subjects with HI/HA syndrome.

Inclusion Criteria:

- Individuals age ≥12 months and ≤40 years

- Diagnosis of HI/HA syndrome

- On diazoxide therapy for treatment of hypoglycemia

- Females ≥11 years of age or menstruating must have a negative urine/serum pregnancy
test and must use an acceptable method of contraception, including abstinence, a
barrier method (diaphragm or condom), Depo-Provera, or an oral contraceptive, for the
duration of the study.

- Informed consent for participants ≥18 years. Parental/guardian permission (informed
consent) and, if appropriate, child assent for participants <18 years.

Exclusion Criteria:

- Individuals age <12 months or >40 years

- Individuals who have experienced an allergic reaction to Vitamin E

- Individuals with a known allergy to dairy, whey, or soy

- On concurrent therapy with a medication known to be metabolized by the CYP3A pathway

- Individuals with a known increased risk of bleeding (bleeding disorder or on
antiplatelet or anticoagulation therapy)

- Vitamin E supplementation within 30 days prior to enrollment, including multivitamins
containing Vitamin E

- Severe hypoglycemia (plasma glucose <50 mg/dL on repeat checks using home glucose
meter) more than once weekly within 30 days prior to enrollment.

- Evidence of a medical condition that might alter results or compromise the
interpretation of results, including active infection, kidney failure, severe liver
dysfunction, severe respiratory or cardiac failure.

- Evidence of severe hematologic abnormality including severe anemia and/or
thrombocytopenia.

- Any investigational drug use within 30 days prior to enrollment.

- Pregnant or lactating females.

- Parents/guardians or subjects who, in the opinion of the Investigator, may be
non-compliant with study schedules or procedures.

- Unable to provide informed consent (e.g. impaired cognition or judgment).

- Parents/guardians or subjects with limited English proficiency.