Epigallocatechin-3-gallate (EGCG) activates AMPK through the inhibition of glutamate dehydrogenase in muscle and pancreatic ß-cells: A potential beneficial effect in the pre-diabetic state?

Abstract

a b s t r a c tGlucose homeostasis is determined by insulin secretion from the ß-cells in pancreatic islets and by glucose uptake in skeletal muscle and other insulin target tissues. While glutamate dehydrogenase (GDH) senses mitochondrial energy supply and regulates insulin secretion, its role in the muscle has not been elucidated. Here we investigated the possible interplay between GDH and the cytosolic energy sensing enzyme 5 -AMP kinase (AMPK), in both isolated islets and myotubes from mice and humans. The green tea polyphenol epigallocatechin-3-gallate (EGCG) was used to inhibit GDH. Insulin secretion was reduced by EGCG upon glucose stimulation and blocked in response to glutamine combined with the allosteric GDH activator BCH (2-aminobicyclo-[2,2,1] heptane-2-carboxylic acid). Insulin secretion was similarly decreased in islets of mice with ß-cell-targeted deletion of GDH (ßGlud1 −/− ). EGCG did not further reduce insulin secretion in the mutant islets, validating its specificity. In human islets, EGCG attenuated both basal and nutrient-stimulated insulin secretion. Glutamine/BCH-induced lowering of AMPK phosphorylation did not operate in ßGlud1 −/− islets and was similarly prevented by EGCG in control islets, while high glucose systematically inactivated AMPK. In mouse C2C12 myotubes, like in islets, the inhibition of AMPK following GDH activation with glutamine/BCH was reversed by EGCG. Stimulation of GDH in primary human myotubes caused lowering of insulin-induced 2-deoxy-glucose uptake, partially counteracted by EGCG. Thus, mitochondrial energy provision through anaplerotic input via GDH influences the activity of the cytosolic energy sensor AMPK. EGCG may be useful in obesity by resensitizing insulin-resistant muscle while blunting hypersecretion of insulin in hypermetabolic states.

Glutamate pathways of the beta-cell and the control of insulin secretion

“…Such an approach has been reported using epigallocatechin-3-gallate (EGCG), a molecule derived from green tea that exhibits different properties, among them to inhibit GDH in the mmolar range [22]. In human pancreatic islets stimulated with high glucose, EGCG lowers insulin secretion along with a decrease of intracellular glutamate [23]. EGCG has been shown to reduce the body weight of obese subjects [24] and of various animal models [25,26], as well as to improve glucose tolerance in diabetic db/db mice [27].…”

Nummularic acid, a triterpenoid, from the medicinal plant Fraxinus xanthoxyloides, induces energy crisis to suppress growth of prostate cancer cells

“…We believe that NA treatment might have resulted in inhibition of GDH activity and thereby accumulation of glutamine/glutamate, which stimulates the AMPK activity. This kind of mechanism was recently shown in myotubes, where EGCG, a well‐known anti‐cancer component of green tea inhibits GDH activity, accumulates glutamine, and thereby uses glutamine to activate AMPK . Whether this is one of mechanism of AMPK activation by NA, remains to be explored.…”

“…This kind of mechanism was recently shown in myotubes, where EGCG, a wellknown anti-cancer component of green tea inhibits GDH activity, accumulates glutamine, and thereby uses glutamine to activate AMPK. 49 Whether this is one of mechanism of AMPK activation by NA, remains to be explored. Overall, our studies show that NA is a novel compound that contains anticancer activity.…”

The Anti-Obesity Effects of Green Tea: A Controlled, Randomized, Clinical Trial

“…Even a short-term ingestion of green tea extract could blunt glycemic response after a postexercise glucose uptake. The suggested mechanism was that skeletal muscle glucose uptake might be altered by green tea supplementation (1,2,(17)(18)(19).…”