Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase

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

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Abstract

Insulin secretion by pancreatic β-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 β-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.

Original languageEnglish (US)
Pages (from-to)10214-10221
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number15
DOIs
StatePublished - Apr 14 2006
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Li, C., Allen, A., Kwagh, J., Doliba, N. M., Qin, W., Najafi, H., Collins, H. W., Matschinsky, F. M., Stanley, C. A., & Smith, T. J. (2006). Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase. Journal of Biological Chemistry, 281(15), 10214-10221. https://doi.org/10.1074/jbc.M512792200