title: Modulation of glutamate generation in mitochondria affects hormone secretion in INS-1E beta cells.
abstract: The mitochondria play a pivotal role in regulating glucose-induced insulin secretion in the pancreatic beta cell. We have recently demonstrated that glutamate derived from mitochondria participates directly in the stimulation of insulin exocytosis. In the present study, mitochondria isolated from the beta cell line INS-1E generated glutamate when incubated with the tricarboxylic acid cycle intermediate succinate. The generation of glutamate correlated with stimulated mitochondrial activity monitored as oxygen consumption and was inhibited by the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone. Glutamate is formed by the mitochondrial enzyme glutamate dehydrogenase from alpha-ketoglutarate. Transient overexpression of glutamate dehydrogenase in INS-1E cells resulted in potentiation of glucose-stimulated hormone secretion without affecting basal release. These results further point to glutamate as an intracellular messenger playing a key role in the control of insulin exocytosis.
authors.affiliation: Department of Internal Medicine, University Medical Center, Geneva, Switzerland. pierre.maechler@medecine.unige.ch
authors.forename: P
authors.initials: P
authors.lastname: Maechler
authors.forename: P A
authors.initials: PA
authors.lastname: Antinozzi
authors.forename: C B
authors.initials: CB
authors.lastname: Wollheim
mesh_terms: D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D005969:Glutamate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005994:Glycerophosphates / Q000494:pharmacology; D006728:Hormones / Q000378:metabolism*; D019382:Human Growth Hormone / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007340:Insulinoma; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D010190:Pancreatic Neoplasms; D051381:Rats; D013386:Succinates / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D005994:Glycerophosphates; D006728:Hormones; D007328:Insulin; D013386:Succinates; D014475:Uncoupling Agents; D019382:Human Growth Hormone; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D018698:Glutamic Acid; C029620:alpha-glycerophosphoric acid; D005969:Glutamate Dehydrogenase; D005947:Glucose; D010100:Oxygen