Treatment prevents hypoglycemia in children with hyperinsulinism

Date:
April 13, 2022
Source:
Children's Hospital of Philadelphia
Summary:
Researchers have shown that a targeted treatment they developed
is effective at controlling blood sugar in patients with
hyperinsulinism (HI), a genetic disease in which the pancreas
produces too much insulin.

The findings provide further evidence that the treatment could
prevent hypoglycemia in patients with HI and may preclude the need
for a full removal of their pancreas, a current standard treatment
for severe diffuse HI.



FULL STORY ========================================================================== Researchers at Children's Hospital of Philadelphia (CHOP) have shown that
a targeted treatment they developed is effective at controlling blood
sugar in patients with hyperinsulinism (HI), a genetic disease in which
the pancreas produces too much insulin. The findings, which were published today in Diabetes Care, provide further evidence that the treatment could prevent hypoglycemia in patients with HI and may preclude the need for a
full removal of their pancreas, a current standard treatment for severe
diffuse HI.


========================================================================== "There are currently very few medical treatments for HI, and those
treatments are of limited effectiveness while also associated
with significant side effects," said senior study author Diva D. De Leo'n-Crutchlow, MD, Chief of the Division of Endocrinology and Diabetes
and Director of the Congenital Hyperinsulinism Center at Children's
Hospital of Philadelphia. "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." Congenital HI is the most common cause of persistent hypoglycemia in
infants and children. Although about half of cases have no known genetic
cause, the most common and severe form of HI is caused by a mutation
in genes that encode the two subunits of the beta-cell ATP-sensitive
potassium channel, a form of the disease known as KATPHI. Patients with
this form of the disease become hypoglycemic when fasting and also after a protein-rich meal, likely due to the glutamine in the protein stimulating
the amplification of glucagon-like peptide-1 (GLP-1) receptor signaling
on the beta-cell.

In prior studies, CHOP researchers have shown that administering
exendin-(9- 39), which blocks the GLP-1 receptor, through an intravenous infusion significantly increased fasting glucose levels in adolescents
and adults with the KATPHI form of the disease. They also showed that the
agent inhibits insulin secretion in models of KATPHI disease. Together,
the results suggested that inhibiting GLP-1 signaling could be an
effective means of controlling HI.

Given the success of prior studies, the researchers decided to test
exendin-(9- 39) in younger children with HI to see if the drug would
have similar success in that population, not only during fasting but
also after a meal. They enrolled 16 patients between the ages of 10
months and 15 years with persistent hypoglycemia due to HI, all but
one of whom had genetically confirmed KATPHI; the one patient without
genetic confirmation had symptoms consistent with KATPHI.

To test the effectiveness of the treatment, the researchers conducted
a six- hour infusion of three different doses of exendin-(9-39) after
patients had been fasting for approximately 12 hours and compared those
effects with that of a control saline solution. Over the period of another
two days, the researchers infused a subset of eight patients with 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 researchers found that exendin-(9-39) resulted in a 76% reduction
in likelihood of fasting hypoglycemia in the mid-dose group and by
84% in the group receiving the highest dose. They found administering exendin-(9-39) during the protein challenge resulted in an 82% reduction
in the likelihood of hypoglycemia. The mid-dose group also demonstrated
a 20% increase in fasting glucose, while the higher dose resulted in
a 28% increase in glucose after a meal and a 30% increase in glucose
after a protein challenge. Of note, while the effect of exendin-(9-39)
on fasting glucose seems to be mediated by suppression of insulin
secretion, the effect on protein-induced hypoglycemia may be mediated by exendin-(9-39)-mediated increase on glucagon, suggesting the treatment
might induce multiple mechanisms of blood sugar control.

"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,"
Dr. De Leo'n- Crutchlow said.

This study was funded by grant 1R01FD004095-01A1 and by The Clifford and Katherine Goldsmith Foundation. The project described was supported by
grant number UL1RR024134 from the National Center for Research Resources.


========================================================================== Story Source: Materials provided by
Children's_Hospital_of_Philadelphia. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Darko Stefanovski, Mary E. Vajravelu, Stephanie Givler, Diva
D. De Leo'n.

Exendin-(9-39) Effects on Glucose and Insulin in Children With
Congenital Hyperinsulinism During Fasting and During a Meal and
a Protein Challenge.

Diabetes Care, 2022; DOI: 10.2337/dc21-2009 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220413130905.htm

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