Green tea polyphenols modulate insulin secretion by inhibiting glutamate dehydrogenase.
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.
Donald Danforth Plant Science Center, 975 Warson Road, St. Louis, MO 63132, USA.
Changhong
C
Li
Aron
A
Allen
Jae
J
Kwagh
Nicolai M
NM
Doliba
Wei
W
Qin
Habiba
H
Najafi
Heather W
HW
Collins
Franz M
FM
Matschinsky
Charles A
CA
Stanley
Thomas J
TJ
Smith
D000244:Adenosine Diphosphate / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005419:Flavonoids / Q000737:chemistry*; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000737:chemistry; D022124:Hyperammonemia / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D007700:Kinetics; D007930:Leucine / Q000737:chemistry; D008297:Male; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D010101:Oxygen Consumption; D010477:Perfusion; D010636:Phenols / Q000737:chemistry*; D059808:Polyphenols; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D013662:Tea; D013997:Time Factors
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007328:Insulin; D010636:Phenols; D059808:Polyphenols; D013662:Tea; D000244:Adenosine Diphosphate; D006160:Guanosine Triphosphate; D000255:Adenosine Triphosphate; D005969:Glutamate Dehydrogenase; D007930:Leucine