Researchers based at the Children’s Hospital of Philadelphia (CHOP) have developed and trialed a candidate treatment for children with congenital hyperinsulinism, which was successful at reducing bouts of low blood sugar, or hypoglycemia, in a phase IIa trial.
Congenital hyperinsulinism is a rare condition affecting less than 1 in 25,000 children. Individuals with this condition have abnormally high levels of insulin determined by inherited genetic mutations. The main symptom is varying degrees of hypoglycemia.
While many of those affected by this condition can manage the symptoms through diet, more serious cases need treatment which can currently involve removal of some or all of their pancreas. There is an ongoing need for better, and less life changing, treatment options for these patients.
The genetics of congenital hyperinsulinism is varied, in line with the varied symptom severity. “There are more than 11 known monogenic causes of hyperinsulinemia, but the underlying genetic cause remains unknown in around 50% of the cases,” write senior author Diva De León-Crutchlow, Chief of the Division of Endocrinology and Diabetes and Director of the Congenital Hyperinsulinism Center at CHOP, and colleagues in the journal Diabetes Care.
De León-Crutchlow and team investigated if a better treatment for children with one of the more common and serious cases of this condition, caused by mutations in the genes ABCC8 and KCNJ11, could be developed.
This type of hyperinsulinism is unresponsive to treatment with diazoxide therapy and is characterized by hypoglycemia after eating protein. The team reasoned that the most likely cause of this was most likely to be “glutamine-stimulated amplification of glucagon-like peptide 1 (GLP-1) receptor signaling.”
They investigated whether an antagonist of GLP-1, exendin-(9-39), could help raise glucose levels in these children. They have previously carried out successful tests in adolescents but this phase IIa study involved 16 children aged 10 months to 15 years with persistent hypoglycemia due to hyperinsulinism.
The risk of fasting hypoglycemia was reduced by 76-84% in these children, across two groups receiving a mid-level and high dose of the treatment. During a protein challenge test, exendin treatment reduced the risk for subsequent hypoglycemia by 82% and a 20-28% increase in fasting glucose was seen in the two treatment groups.
“There are currently very few medical treatments for hyperinsulinism, and those treatments are of limited effectiveness while also associated with significant side effects,” said De León-Crutchlow, in a press statement.
“This study is further evidence supporting the use of exendin-(9-39), which has been granted breakthrough therapy designation for the treatment of hyperinsulinism, and we look forward to moving this therapy into a phase III trial,” De León-Crutchlow said.
