Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase.

Abstract

Insulin secretion by pancreatic beta-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 ED(50) 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 beta-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.

• Authors: 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
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 15 Pg. 10214-21 (Apr 14 2006) ISSN: 0021-9258 [Print] United States
• PMID: 16476731 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Flavonoids
• Insulin
• Phenols
• Polyphenols
• Tea
• Adenosine Diphosphate
• Guanosine Triphosphate
• Adenosine Triphosphate
• Glutamate Dehydrogenase
• Leucine

Topics

• Adenosine Diphosphate (chemistry)
• Adenosine Triphosphate (chemistry)
• Animals
• Cattle
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Flavonoids (chemistry)
• Glutamate Dehydrogenase (antagonists & inhibitors, metabolism)
• Guanosine Triphosphate (chemistry)
• Hyperammonemia (metabolism)
• Insulin (metabolism)
• Insulin Secretion
• Insulin-Secreting Cells (metabolism)
• Islets of Langerhans (metabolism)
• Kinetics
• Leucine (chemistry)
• Male
• Models, Biological
• Models, Chemical
• Models, Molecular
• Oxygen Consumption
• Perfusion
• Phenols (chemistry)
• Polyphenols
• Protein Conformation
• Rats
• Rats, Wistar
• Tea
• Time Factors