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Treatment prevents hypoglycaemia in children with hyperinsulinism

A recent study says targeted treatment could prevent hypoglycaemia in patients with hyperinsulinism (HI) and prevent the removal of their pancreas, an existing standard treatment for severe HI.

Researchers at the Children’s Hospital of Philadelphia (CHOP) found that exendin-(9-39), which blocks the GLP-1 receptor, is successful in preventing fasting and protein-induced hypoglycaemia in children with HI, a genetic disease when the pancreas produces too much insulin.

Senior study author Diva D. De León-Crutchlow, MD, Chief of the Division of Endocrinology and Diabetes and Director of the Congenital Hyperinsulinism Center at Children’s Hospital of Philadelphia, said: “There are currently very few medical treatments for HI, and those treatments are of limited effectiveness while also associated with significant side effects.

“We are very excited about this study because by targeting the underlying pathophysiology, exendin-(9-39) offers potential therapeutic advantages over currently available therapies for HI, which could make a huge difference in the lives of the children we care for.”

The most prominent cause of persistent hypoglycaemia in infants and children is congenital HI. Despite half the cases of HI having no genetic cause, the most common and severe form of HU is due to a mutation in genes “that encode the two subunits of the beta-cell ATP-sensitive potassium channel”, which is a form of the disease known as KATPHI.

Patients with KATPHI become hypoglycaemic when fasting and after a protein-rich meal. This is probably due to “the glutamine in the protein stimulating the amplification of glucagon-like peptide-1 (GLP-1) receptor signalling on the beta-cell”.

CHOP researchers have previously found that administering exendin-(9-39), blocking the GLP-1 receptor, via an intravenous infusion majorly increased fasting glucose levels in adolescents and adults with KATPHI. The researchers also demonstrated that the agent inhibits insulin secretion in models of KATPHI disease. Both of these findings indicated that inhibiting GLP-1 signalling could be an effective way of controlling HI.

Due to the findings of previous studies, the researchers tested exendin-(9-39) in younger children with HI to assess whether the drug would produce similar success during fasting and after a meal.

The study involved 16 participants from 10-months-old to 15-years-old with persistent hypoglycaemia due to HI and genetically confirmed KATPHI. One participant had symptoms consistent with KATPHI but no genetic confirmation.

The participants received a six-hour infusion of three different doses of exendin-(9-39) after fasting for around 12 hours and the results were compared to those of a control saline solution.

Eight participants then received either the highest dose of exendin-(9-39) or a saline control solution during a mixed meal tolerance test and an oral protein tolerance test.

The findings showed that:

  • Exendin-(9-39) resulted in a 76 per cent reduction in probability of fasting hypoglycaemia in the mid-dose group and by 84 per cent in the group receiving the highest dose.
  • Administering exendin-(9-39) during the protein challenge resulted in an 82 per cent reduction in the probability of hypoglycaemia.
  • The mid-dose group demonstrated a 20 per cent increase in fasting glucose.
  • The higher dose resulted in a 28 per cent increase in glucose after a meal and a 30 per cent increase in glucose after a protein challenge.

The study noted: “While the effect of exendin-(9-39) on fasting glucose seems to be mediated by suppression of insulin secretion, the effect on protein-induced hypoglycaemia may be mediated by exendin-(9-39)-mediated increase on glucagon, suggesting the treatment might induce multiple mechanisms of blood sugar control.”

Dr De León-Crutchlow concluded: “This study is further evidence supporting the use of exendin-(9-39), which has been granted breakthrough therapy designation for the treatment of HI, and we look forward to moving this therapy into a phase 3 trial.”

The study was published in the journal Diabetes Care.

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