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M512792200v1
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Papers In Press, published online ahead of print February 13, 2006
J. Biol. Chem, 10.1074/jbc.M512792200
Submitted on November 30, 2005
Revised on January 26, 2006
Accepted on February 13, 2006

Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase

Changhong Li, Aron Allen, Jae Kwagh, Nicolai Doliba, Wei Qin, Habiba Najafi, Heather W. Collins, Franz M. Matschinsky, Charles A. Stanley, and Thomas J. Smith

Donald Danforth Plant Science Center, Saint Louis, MO 63132

Corresponding Author: tsmith{at}danforthcenter.org

Insulin secretion by pancreatic ß-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 (1-3). The importance of GDH was underscored by features of the hyperinsulism/ hyperammonemia (HI/HA) syndrome where a dominant mutation causes the loss of inhibition by GTP and ATP (4-6). Here we report the effects of green tea polyphenols on glutamate dehydrogenase and insulin secretion. Of the four compounds tested, EGCG and ECG were found to inhibit the enzyme with nanomolar ED50’s and therefore as potent as the physiologically important inhibitor, GTP. Furthermore, we demonstrate that EGCG inhibits leucine 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 further show that these compounds act in an allosteric manner independent of their antioxidant activity and that the ß-cell stimulatory effects are directly correlated with glutamine oxidation. These results demonstrate that EGCG can facilitate dissecting the complex regulation of insulin secretion by pharmacologically modulating the effects of GDH.




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