title: 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: Glucose 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.
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva Medical Center, 1 rue Michel-Servet, 1206 Geneva, Switzerland; Faculty Diabetes Center, University of Geneva Medical Center, 1 rue Michel-Servet, 1206 Geneva, Switzerland.
authors.forename: Shirin
authors.initials: S
authors.lastname: Pournourmohammadi
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva Medical Center, 1 rue Michel-Servet, 1206 Geneva, Switzerland; Faculty Diabetes Center, University of Geneva Medical Center, 1 rue Michel-Servet, 1206 Geneva, Switzerland.
authors.forename: Mariagrazia
authors.initials: M
authors.lastname: Grimaldi
authors.affiliation: Department of Drug Design and Pharmacotherapy, Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark.
authors.forename: Malin H
authors.initials: MH
authors.lastname: Stridh
authors.affiliation: Faculty Diabetes Center, University of Geneva Medical Center, 1 rue Michel-Servet, 1206 Geneva, Switzerland; Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Lavallard
authors.affiliation: Department of Drug Design and Pharmacotherapy, Faculty of Health and Medical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark.
authors.forename: Helle S
authors.initials: HS
authors.lastname: Waagepetersen
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva Medical Center, 1 rue Michel-Servet, 1206 Geneva, Switzerland; Faculty Diabetes Center, University of Geneva Medical Center, 1 rue Michel-Servet, 1206 Geneva, Switzerland.
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva Medical Center, 1 rue Michel-Servet, 1206 Geneva, Switzerland; Faculty Diabetes Center, University of Geneva Medical Center, 1 rue Michel-Servet, 1206 Geneva, Switzerland. Electronic address: Pierre.Maechler@unige.ch.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maechler
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism; D005969:Glutamate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism; D009132:Muscles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011236:Prediabetic State / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D002392:Catechin; C045651:epigallocatechin gallate; D005969:Glutamate Dehydrogenase; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D002118:Calcium
keywords: AMPK; Beta-cell; EGCG; Glutamate dehydrogenase; Green tea; Insulin secretion; Muscle cells; Pancreatic islet