Investigators will assess the tolerability of oral Vitamin E supplementation in subjects with congenital hyperinsulinism (HI) and hyperammonemia (HA) 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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
14
Subjects will take an oral Vitamin E (alpha-tocopherol) supplement once daily with a fat-containing meal for 2 weeks. The dose will be based on subject age (150 IU if 1-3 years old, 300 IU if 4-8 years old, 450 IU if 9-17 years old, 600 IU if \>17 years old). Formulations include 50 IU/mL liquid and 200 IU capsules. The liquid formulation will be used for subjects who will receive \<600 IU daily, or for any subjects who prefer liquid medication to capsules.
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Tolerability of Vitamin E Based on Responses to a Subject/Parent-reported Symptom Questionnaire After Vitamin E Supplementation Compared to Baseline
The following symptoms will be scored as either "none" (did not occur)=0, "mild" (minimal symptoms, no treatment needed)=1, "moderate" (symptoms requiring treatment at home or as an outpatient=2, or "severe" (symptoms requiring hospitalization or emergency room visit, or life-threatening or potentially life-threatening symptoms)=4: Seizure, Headache, Vision change/blurred vision, Weakness, Fatigue, Nausea, Vomiting, Diarrhea, Stomach pain, Constipation, Bruising, Bleeding, Rash, Itching, Other Symptom scores will be summed to yield a Tolerability Questionnaire Score for each participant. The Tolerability Questionnaire Score has a minimum score of 0 (symptoms did not occur) and a maximum score of 60 (all of the measured symptoms occurred, each with severe designation). The number (count) of participants with an increase in Tolerability Questionnaire Score from baseline to 2 weeks (following Vitamin E supplementation) will be reported.
Time frame: 2 weeks
Plasma Alpha-tocopherol Concentration
change in fasting plasma alpha-tocopherol concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Delta-plasma Glucose Concentration
change in delta-glucose concentration (fasting plasma glucose - nadir plasma glucose during oral protein tolerance test) following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Fasting Plasma Glucose Concentration
change in fasting plasma glucose concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Nadir Plasma Glucose Concentration
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change in nadir plasma glucose concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Fasting Plasma Insulin Concentration
change in fasting plasma insulin concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Peak Plasma Insulin Concentration
change in peak plasma insulin concentration during oral protein tolerance test following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Delta-plasma Insulin Concentration
change in delta-plasma insulin concentration (peak plasma insulin - fasting plasma insulin during oral protein tolerance test) following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Fasting Plasma Ammonia Concentration
change in fasting plasma ammonia concentration following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Delta-plasma Ammonia Concentration
change in delta-plasma ammonia concentration (plasma ammonia at 60 minutes - fasting plasma ammonia during oral protein tolerance test) following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks
Hypoglycemia Frequency
change in frequency of hypoglycemia (plasma glucose \<70 mg/dL) detected on home glucose meter following Vitamin E supplementation (2 weeks \[visit 2\] - baseline \[visit 1\])
Time frame: 2 weeks