Congenital hyperinsulinism is a rare, inherited disease affecting about 1 in 25,000 to 1 in 50,000 infants. In this disorder, the beta cells (cells that produce insulin) in the pancreas produce too much insulin and at the wrong time, leading to low blood sugar. Four types of congenital hyperinsulinism are known, caused by different genetic mutations. The disease can be difficult to identify in babies because the symptoms include irritability, sleepiness, lethargy and excessive hunger, but in severe cases, it can be life threatening, with seizures and coma. Current treatments include feeding more sugar, medication to control insulin secretion and surgery to remove part of the pancreas. These researchers are working on a drug to treat one type of congenital hyperinsulinism that does not respond to any current medication and is typically treated by near-total removal of the infant’s pancreas. The new drug acts by blocking the activity of a protein called glucagon-like peptide-1 receptor, reducing insulin secretion.
Congenital hyperinsulinism due to mutations in the KATP channel (KATPHI) is characterized by severe hypoglycemia unresponsive to available medical therapy. Currently, most patients require a near-total pancreatectomy to control the hypoglycemia, resulting in prolonged hospital stays and high risk for life-threatening complications. Antagonism of the glucagon-like peptide-1 receptor by exendin-(9-39) results in elevation of fasting blood glucose levels in mice, in baboons and in healthy human subjects. Our preliminary data demonstrate that exendin-(9-39) inhibits insulin secretion and corrects fasting hypoglycemia in a mouse model of congenital hyperinsulinism (SUR-1−/− mice). In isolated islets from these mice, exendin-(9-39) suppresses baseline and amino acid–stimulated insulin secretion. Preliminary results from a pilot study show that an intravenous infusion of exendin-(9-39) in adult human subjects with KATPHI suppresses insulin secretion and raises fasting blood glucose levels. Our long-term objective is to develop exendin-(9-39) as a new therapy for the treatment of congenital hyperinsulinism. Our overall hypothesis is that antagonism of the GLP-1 receptor by exendin-(9-39) will increase fasting blood glucose levels, prevent protein-induced hypoglycemia and decrease glucose requirement to maintain euglycemia in subjects with KATPHI as a result of suppressed insulin secretion and increased glucagon levels. The assistance requested in this proposal will allow us to proceed with further pre-clinical and clinical studies in the pathway of development of this potential new treatment. Although congenital hyperinsulinism due to mutations in the KATP channel is a rare disease affecting approximately 1:20,000 to 1:50,000 children in this country, this devastating disease and its current treatment (near-total pancreatectomy) are associated with severe, life-threatening complications that could be prevented with effective medical therapy.
The development of exendin-(9-39) as a therapeutic agent for this disorder would represent a major breakthrough in the field. Furthermore, the outcomes of this translational research project may have implications for treatment of other forms of hyperinsulinism and other forms of hypoglycemia in which GLP-1 may play a role, including post-prandial hypoglycemia after Nissen fundoplication and gastric bypass surgery.
Children’s Hospital of Philadelphia
Diva D. De Leon, M.D.
Children’s Hospital of Philadelphia/University of Pennsylvania
Charles A. Stanley, M.D.
Public Health Impact
Currently, there is no effective medical therapy for subjects with congenital hyperinsulinism due to mutations in the KATP channel. Our preliminary results show very promising effects of antagonism of the GLP-1 receptor by exendin-(9-39) on glucose homeostasis of mice and human subjects with KATP channel mutations.
Work on this project is complete. The investigators used BrIDGs data to amend an Investigational New Drug (IND) application that was cleared by the Food and Drug Administration, allowing clinical trials to begin.
- Synthesis of Good Manufacturing Practice (GMP) and non-GMP material
- Formulation development
- Pharmacokinetic/absorption, distribution, metabolism, and excretion (PK/ADME) studies
- IND-directed toxicology