Green Tea Polyphenols Modulate Insulin Secretion by Inhibiting Glutamate Dehydrogenase

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2006; 281(15):10214-21. DOI: 10.1074/jbc.M512792200
Source: PubMed


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.

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    • "Currently, the only reported GDH1 inhibitor is epigallocatechin gallate (EGCG), a polyphenol flavonoid isolated from green tea. However, EGCG targets a group of enzymes that use NADPH as a cofactor (Li et al., 2006, 2011a, 2011b). We thus designed a series of screening assays to identify GDH1-selective inhibitors . "
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    • "In retrospect , the participation of glutamate dehydrogenase in the control of autophagy is in agreement with the obser - vation that autophagy was stimulated pharmacologically by the green tea component epigallocatechin gallate ( Li et al . 2011 ; Zhou et al . 2014 ) . This compound is a powerful inhib - itor of glutamate dehydrogenase ( Li et al . 2006 ) , but the link between these phenomena was not made . Involvement of GDH in amino acid sensing has serious consequences for the use of chloroquine in the measure - ment of autophagic flux . This compound not only increases the intralysosomal pH and in this way affects the intralysosomal amino acid pool , as discussed above ( cf . sect"
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