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J. Biol. Chem., Vol. 281, Issue 15, 10214-10221, April 14, 2006
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1
From the
Donald Danforth Plant Science Center, St. Louis, Missouri 63132, Endocrinology Division, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, and ¶Diabetes Research Center and Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Insulin secretion by pancreatic 
-cells is stimulated by glucose, amino acids, and other metabolic fuels. Glutamate dehydrogenase (GDH) has been shown to play a regulatory role in this process. The importance of GDH was underscored by features of hyperinsulinemia/hyperammonemia syndrome, where a dominant mutation causes the loss of inhibition by GTP and ATP. Here we report the effects of green tea polyphenols on GDH and insulin secretion. Of the four compounds tested, epigallocatechin gallate (EGCG) and epicatechin gallate were found to inhibit GDH with nanomolar ED50 values and were therefore found to be as potent as the physiologically important inhibitor GTP. Furthermore, we have demonstrated that EGCG inhibits BCH-stimulated insulin secretion, a process that is mediated by GDH, under conditions where GDH is no longer inhibited by high energy metabolites. EGCG does not affect glucose-stimulated insulin secretion under high energy conditions where GDH is probably fully inhibited. We have further shown that these compounds act in an allosteric manner independent of their antioxidant activity and that the -cell stimulatory effects are directly correlated with glutamine oxidation. These results demonstrate that EGCG, much like the activator of GDH (BCH), can facilitate dissecting the complex regulation of insulin secretion by pharmacologically modulating the effects of GDH.
Received for publication, November 30, 2005 , and in revised form, January 26, 2006.
* This work was supported by National Institutes of Health (NIH) Grant DK072171 (to T. J. S.), NIH Grant DK53012 and American Diabetes Association Research Award 1-05-RA-128 (to C. A. S. and C. L.), NIH Grant DK22122 (to F. M. M.), and NIH Grant DK19525 for islet biology and radioimmunoassay cores. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom correspondence should be addressed: Donald Danforth Plant Science Ctr., 975 N. Warson Rd., St. Louis, MO 63132. Tel.: 314-587-1451; Fax: 314-587-1551; E-mail: tsmith{at}danforthcenter.org.
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