title: Insulin secretion is controlled by mGlu5 metabotropic glutamate receptors.
abstract: Recent evidence suggests that metabotropic glutamate (mGlu) receptors are involved in the regulation of hormone secretion in the endocrine pancreas. We report here that endogenous activation of mGlu5 receptors is required for an optimal insulin response to glucose both in clonal beta-cells and in mice. In clonal beta-cells, mGlu5 receptors were expressed at the cell surface and were also found in purified insulin-containing granules. These cells did not respond to a battery of mGlu5 receptor agonists that act extracellularly, but instead responded to a cell-permeant analog of glutamate with an increase in [Ca2+]i and insulin secretion. Both effects were largely attenuated by the mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP). MPEP and its structural analog, (E)-2-methyl-6-styryl-pyridine (SIB-1893), reduced the increase in [Ca2+]i and insulin secretion induced by glucose in clonal beta-cells, whereas a mGlu1 receptor antagonist was inactive. mGlu5 knockout mice showed a defective insulin response at all times after a glucose pulse (1.5 g/kg, i.p.), whereas wild-type mice treated with MPEP (10 mg/kg, i.p.) showed a selective impairment in the late phase of insulin secretion in response to glucose challenge. Mice injected with MPEP or lacking mGlu5 receptors also showed a blunted glucagon response to an insulin challenge. We conclude that insulin secretion is under the control of mGlu5 receptors both in clonal beta-cells and in vivo. Drugs that modulate the function of mGlu5 receptors might affect glucose homeostasis by altering the secretion of pancreatic hormones.
authors.affiliation: I.N.M. Neuromed, Pozzilli, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Storto
authors.forename: Loredana
authors.initials: L
authors.lastname: Capobianco
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Gemma
authors.initials: G
authors.lastname: Molinaro
authors.forename: Roberto
authors.initials: R
authors.lastname: Gradini
authors.forename: Barbara
authors.initials: B
authors.lastname: Riozzi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Mambro
authors.forename: Kathryn J
authors.initials: KJ
authors.lastname: Mitchell
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
authors.forename: Maria P
authors.initials: MP
authors.lastname: Vairetti
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D018345:Mice, Knockout; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D005947:Glucose