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. Pre-clinical data show that vitamin E inhibits GDH activity in human cell
lines and improves fasting hypoglycemia in a GDH HI mouse model. Pilot study data show that
vitamin E supplementation with a moderate dose is well-tolerated in children and adults with
HI/HA syndrome, while continuing diazoxide treatment. However, most subjects continued to
exhibit protein-induced hyperinsulinemic hypoglycemia. We hypothesize that a higher vitamin E
dose will inhibit GDH over-activity in subjects with HI/HA syndrome, resulting in improved
hyperinsulinemic hypoglycemia, reduced blood ammonia concentration, and decreased seizure
activity.
Phase:
Phase 2
Details
Lead Sponsor:
Children's Hospital of Philadelphia
Collaborators:
Lawson Wilkins Pediatric Endocrine Society University of Pennsylvania