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Am J Physiol Endocrinol Metab 286: E280-E285, 2004. First published October 7, 2003; doi:10.1152/ajpendo.00380.2003
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Overexpression of constitutively activated glutamate dehydrogenase induces insulin secretion through enhanced glutamate oxidation

Takatoshi Anno,1 Shunsuke Uehara,2 Hideki Katagiri,3 Yasuharu Ohta,1 Kohei Ueda,1 Hiroyuki Mizuguchi,4 Yoshinori Moriyama,2 Yoshitomo Oka,3 and Yukio Tanizawa1

1Division of Molecular Analysis of Human Disorders, Department of Bio-Signal Analysis, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505; 2Department of Biochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Okayama 700-8530; 3Division of Molecular Metabolism and Diabetes, Department of Internal Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8574; and 4Division of Cellular and Gene Therapy Products, National Institute of Health Sciences, Tokyo 158-8501, Japan

Submitted 25 August 2003 ; accepted in final form 2 October 2003

Glutamate dehydrogenase (GDH) catalyzes reversible oxidative deamination of L-glutamate to {alpha}-ketoglutarate. Enzyme activity is regulated by several allosteric effectors. Recognition of a new form of hyperinsulinemic hypoglycemia, hyperinsulinism/hyperammonemia (HI/HA) syndrome, which is caused by gain-of-function mutations in GDH, highlighted the importance of GDH in glucose homeostasis. GDH266C is a constitutively activated mutant enzyme we identified in a patient with HI/HA syndrome. By overexpressing GDH266C in MIN6 mouse insulinoma cells, we previously demonstrated unregulated elevation of GDH activity to render the cells responsive to glutamine in insulin secretion. Interestingly, at low glucose concentrations, basal insulin secretion was exaggerated in such cells. Herein, to clarify the role of GDH in the regulation of insulin secretion, we studied cellular glutamate metabolism using MIN6 cells overexpressing GDH266C (MIN6-GDH266C). Glutamine-stimulated insulin secretion was associated with increased glutamine oxidation and decreased intracellular glutamate content. Similarly, at 5 mmol/l glucose without glutamine, glutamine oxidation also increased, and glutamate content decreased with exaggerated insulin secretion. Glucose oxidation was not altered. Insulin secretion profiles from GDH266C-overexpressing isolated rat pancreatic islets were similar to those from MIN6-GDH266C, suggesting observation in MIN6 cells to be relevant in native {beta}-cells. These results demonstrate that, upon activation, GDH oxidizes glutamate to {alpha}-ketoglutarate, thereby stimulating insulin secretion by providing the TCA cycle with a substrate. No evidence was obtained supporting the hypothesis that activated GDH produced glutamate, a recently proposed second messenger of insulin secretion, by the reverse reaction, to stimulate insulin secretion.

hypoglycemia; hyperinsulinism/hyperammonemia syndrome; islet of Langerhans


Address for reprint requests and other correspondence: Y. Tanizawa, Div. of Molecular Analysis of Human Disorders, Dept. of Bio-Signal Analysis, Yamaguchi Univ. Graduate School of Medicine, Minami-Kogushi Ube, Yamaguchi 755-8505, Japan (E-mail: tanizawa{at}yamaguchi-u.ac.jp).




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