title: Glutamate inhibits protein phosphatases and promotes insulin exocytosis in pancreatic beta-cells.
abstract: In human type 2 diabetes mellitus, loss of glucose-sensitive insulin secretion from the pancreatic beta-cell is an early pathogenetic event, but the mechanisms involved in glucose sensing are poorly understood. A messenger role has been postulated for L-glutamate in linking glucose stimulation to sustained insulin exocytosis in the beta-cell, but the precise nature by which L-glutamate controls insulin secretion remains elusive. Effects of L-glutamate on the activities of ser/thr protein phosphatases (PPase) and Ca(2+)-regulated insulin exocytosis in INS-1E cells were investigated. Glucose increases L-glutamate contents and promotes insulin secretion from INS-1E cells. L-glutamate also dose-dependently inhibits PPase enzyme activities analogous to the specific PPase inhibitor, okadaic acid. L-glutamate and okadaic acid directly and non-additively promote insulin exocytosis from permeabilized INS-1E cells in a Ca(2+)-independent manner. Thus, an increase in phosphorylation state, through inhibition of protein dephosphorylation by glucose-derived L-glutamate, may be a novel regulatory mechanism linking glucose sensing to sustained insulin exocytosis.
authors.affiliation: Karolinska Institutet, Department of Internal Medicine, Stockholm South Hospital, SE-118 83 Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Lehtihet
authors.forename: Dominic-Luc
authors.initials: DL
authors.lastname: Webb
authors.forename: Richard E
authors.initials: RE
authors.lastname: Honkanen
authors.forename: Ake
authors.initials: A
authors.lastname: Sjöholm
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats
chemical_list: D007328:Insulin; D019319:Okadaic Acid; D018698:Glutamic Acid; D010749:Phosphoprotein Phosphatases; D005947:Glucose; D002118:Calcium