Enzyme Defect Leads To Hyperinsulinism

Congenital hyperinsulinism is a group of genetic disorders that cause hypoglycemia in infants and children. "The hypoglycemia is quite dangerous and can cause seizures and permanent brain damage if not promptly detected and treated," says Charles A. Stanley, of the Children's Hospital of Philadelphia. "In its various forms, congenital hyperinsulinism is the most common and most difficult cause of hypoglycemia in young infants."

The majority of cases of congenital hyperinsulinism appear to be due to defects in insulin secretion by pancreatic cells. Currently, it is thought that mutations in any of four different genes can cause the disorder. One of these genes codes for an enzyme called glutamate dehydrogenase. This enzyme is stimulated by the amino acid leucine, meaning that protein meals that contain leucine lead to activation of glutamate dehydrogenase, which in turn triggers the release of insulin from pancreatic cells.

"The glutamate dehydrogenase mutations that cause hyperinsulinism are amino acid mis-sense mutations that impair the sensitivity of the enzyme to inhibition," explains Stanley. "As a result, glutamate dehydrogenase enzyme activity cannot be turned off and this leads to excessive release of insulin and hypoglycemia."

In order to understand how amino acids stimulate insulin and the role of glutamate dehydrogenase in this pathway, Stanley and his colleagues at the University of Pennsylvania generated transgenic mice that had a mutation in their gene for glutamate dehydrogenase. The resulting mice had hypoglycemia, confirming that the mutation can cause disease.

"By over-expressing the mutant form of glutamate dehydrogenase in pancreatic islets, we were able to show that increased glutamate dehydrogenase enzyme activity leads to increased insulin release in the presence of amino acids," says Stanley. "These results were necessary to demonstrate that the mutations of glutamate dehydrogenase which we have found in patients are indeed responsible for causing disease. In addition, they provide an understanding of precisely how amino acids derived from dietary protein exert their effects of controlling insulin."

The results of this study have potential for many therapeutic and diagnostic applications according to Stanley. "The results firmly establish how glutamate dehydrogenase mutations cause hyperinsulinism and provide potential targets for development of new drugs, such as inhibitors of the enzyme, which might be used to treat patients. The results also provide support for using genetic mutation analysis of glutamate dehydrogenase to help diagnose children with hyperinsulinism. Broader implications of the results include the possibility that glutamate dehydrogenase or enzymes in the pathways of amino acid stimulated insulin secretion could serve as targets for drugs to treat diabetes," concludes Stanley.

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