title: The PACAP-regulated gene selenoprotein T is abundantly expressed in mouse and human β-cells and its targeted inactivation impairs glucose tolerance.
abstract: Selenoproteins are involved in the regulation of redox status, which affects several cellular processes, including cell survival and homeostasis. Considerable interest has arisen recently concerning the role of selenoproteins in the regulation of glucose metabolism. Here, we found that selenoprotein T (SelT), a new thioredoxin-like protein of the endoplasmic reticulum, is present at high levels in human and mouse pancreas as revealed by immunofluorescence and quantitative PCR. Confocal immunohistochemistry studies revealed that SelT is mostly confined to insulin- and somatostatin-producing cells in mouse and human islets. To elucidate the role of SelT in β-cells, we generated, using a Cre-Lox strategy, a conditional pancreatic β-cell SelT-knockout C57BL/6J mice (SelT-insKO) in which SelT gene disruption is under the control of the rat insulin promoter Cre gene. Glucose administration revealed that male SelT-insKO mice display impaired glucose tolerance. Although insulin sensitivity was not modified in the mutant mice, the ratio of glucose to insulin was significantly higher in the SelT-insKO mice compared with wild-type littermates, pointing to a deficit in insulin production/secretion in mutant mice. In addition, morphometric analysis showed that islets from SelT-insKO mice were smaller and that their number was significantly increased compared with islets from their wild-type littermates. Finally, we found that SelT is up-regulated by pituitary adenylate cyclase-activating polypeptide (PACAP) in β-pancreatic cells and that SelT could act by facilitating a feed-forward mechanism to potentiate insulin secretion induced by the neuropeptide. Our findings are the first to show that the PACAP-regulated SelT is localized in pancreatic β- and δ-cells and is involved in the control of glucose homeostasis.
authors.affiliation: INSERM U982, Neuronal and Neuroendocrine Differentiation and Communication Laboratory, Sciences Faculty, University of Rouen, Place Emile Blondel, 76 821 Mont-Saint-Aignan cedex, France. youssef.anouar@univ-rouen.fr.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Prevost
authors.forename: Arnaud
authors.initials: A
authors.lastname: Arabo
authors.forename: Long
authors.initials: L
authors.lastname: Jian
authors.forename: Eddy
authors.initials: E
authors.lastname: Quelennec
authors.forename: Dorthe
authors.initials: D
authors.lastname: Cartier
authors.forename: Sahar
authors.initials: S
authors.lastname: Hassan
authors.forename: Anthony
authors.initials: A
authors.lastname: Falluel-Morel
authors.forename: Yannick
authors.initials: Y
authors.lastname: Tanguy
authors.forename: Sophia
authors.initials: S
authors.lastname: Gargani
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lihrmann
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.forename: Hervé
authors.initials: H
authors.lastname: Lefebvre
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.forename: Youssef
authors.initials: Y
authors.lastname: Anouar
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002460:Cell Line; D003433:Crosses, Genetic; D005786:Gene Expression Regulation; D020868:Gene Silencing; D018149:Glucose Intolerance / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics / Q000378:metabolism*; D051140:Selenoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019864:Somatostatin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D046509:Tissue Culture Techniques
chemical_list: C495401:ADCYAP1 protein, human; C495402:Adcyap1 protein, mouse; D001786:Blood Glucose; D007328:Insulin; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; C495235:SELENOT protein, human; D051140:Selenoproteins; C547431:selenoprotein T, mouse