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This Article Full Text Full Text (PDF) All Versions of this Article: 90/3/862S    most recent ajcn.2009.27462AAv1 Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stanley, C. A Search for Related Content PubMed PubMed Citation Articles by Stanley, C. A Agricola Articles by Stanley, C. A

Regulation of glutamate metabolism and insulin secretion by glutamate dehydrogenase in hypoglycemic children^1,2,3,4

¹ From the Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, PA.

² Presented at the "100th Anniversary Symposium of Umami Discovery: The Roles of Glutamate in Taste, Gastrointestinal Function, Metabolism, and Physiology," held in Tokyo, Japan, 10–13 September 2008.

³ Supported by the NIH (RO1-DK56268, RO1-DK53012, UL1-RRO24134, RO1-DK072171), the American Diabetes Association (1-05-RA-128), and the Ajinomoto Amino Acid Research Program. The Ajinomoto Company is a manufacturer of food and amino acids including glutamate.

⁴ Address correspondence requests for reprints to CA Stanley, Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. E-mail: stanleyc{at}email.chop.edu.

In addition to its extracellular roles as a neurotransmitter/sensory molecule, glutamate serves important intracellular signaling functions via its metabolism through glutamate dehydrogenase (GDH). GDH is a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate to -ketoglutarate in a limited number of tissues in humans, including the liver, the kidney, the brain, and the pancreatic islets. GDH activity is subject to complex regulation by negative (GTP, palmitoyl-coenzyme A) and positive (ADP, leucine) allosteric effectors. This complex regulation allows GDH activity to be modulated by changes in energy state and amino acid availability. The importance of GDH regulation has been highlighted by the discovery of a novel hypoglycemic disorder in children, the hyperinsulinism-hyperammonemia syndrome, which is caused by dominantly expressed, activating mutations of the enzyme that impair its inhibition by GTP. Affected children present in infancy with hypoglycemic seizures after brief periods of fasting or the ingestion of a high-protein meal. Patients have characteristic persistent 3- to 5-fold elevations of blood ammonia concentrations but do not display the usual neurologic symptoms of hyperammonemia. The mutant GDH enzyme shows impaired responses to GTP inhibition. Isolated islets from mice that express the mutant GDH in pancreatic β cells show an increased rate of glutaminolysis, increased insulin release in response to glutamine, and increased sensitivity to leucine-stimulated insulin secretion. The novel hyperinsulinism-hyperammonemia syndrome indicates that GDH-catalyzed glutamate metabolism plays important roles in 3 tissues: in β cells, the regulation of amino acid–stimulated insulin secretion; in hepatocytes, the modulation of amino acid catabolism and ammoniagenesis; and in brain neurons, the maintenance of glutamate neurotransmitter concentrations.

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