title: Heterozygous inactivation of plasma membrane Ca(2+)-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability.
abstract: OBJECTIVE
  Calcium plays an important role in the process of glucose-induced insulin release in pancreatic beta cells. These cells are equipped with a double system responsible for Ca(2+) extrusion--the Na/Ca exchanger (NCX) and the plasma membrane Ca(2+)-ATPase (PMCA). We have shown that heterozygous inactivation of NCX1 in mice increased glucose-induced insulin release and stimulated beta cell proliferation and mass. In the present study, we examined the effects of heterozygous inactivation of the PMCA on beta cell function.
  
  
  METHODS
  Biological and morphological methods (Ca(2+) imaging, Ca(2+) uptake, glucose metabolism, insulin release and immunohistochemistry) were used to assess beta cell function and proliferation in Pmca2 (also known as Atp2b2) heterozygous mice and control littermates ex vivo. Blood glucose and insulin levels were also measured to assess glucose metabolism in vivo.
  
  
  RESULTS
  Pmca (isoform 2) heterozygous inactivation increased intracellular Ca(2+) stores and glucose-induced insulin release. Moreover, increased beta cell proliferation, mass, viability and islet size were observed in Pmca2 heterozygous mice. However, no differences in beta cell glucose metabolism, proinsulin immunostaining and insulin content were observed.
  
  
  CONCLUSIONS
  The present data indicates that inhibition of Ca(2+) extrusion from the beta cell and its subsequent intracellular accumulation stimulates beta cell function, proliferation and mass. This is in agreement with our previous results observed in mice displaying heterozygous inactivation of NCX, and indicates that inhibition of Ca(2+) extrusion mechanisms by small molecules in beta cells may represent a new approach in the treatment of type 1 and type 2 diabetes.
authors.affiliation: Laboratoire de Pharmacodynamie et de Thérapeutique, Bâtiment GE, Faculté de Médecine, Université Libre de Bruxelles (ULB), route de Lennik 808, B-1070, Bruxelles, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pachera
authors.affiliation: Laboratoire de Pharmacodynamie et de Thérapeutique, Bâtiment GE, Faculté de Médecine, Université Libre de Bruxelles (ULB), route de Lennik 808, B-1070, Bruxelles, Belgium.
authors.forename: Julien
authors.initials: J
authors.lastname: Papin
authors.affiliation: Laboratoire de Pharmacodynamie et de Thérapeutique, Bâtiment GE, Faculté de Médecine, Université Libre de Bruxelles (ULB), route de Lennik 808, B-1070, Bruxelles, Belgium.|Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Zummo
authors.affiliation: Department of Pathology, Faculty of Medicine, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: Rahier
authors.affiliation: Veterinary and Agrochemical Research Centre, VAR-CODA-CERVA, Brussels, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Mast
authors.affiliation: ULB Center for Diabetes Research, Faculté de Médecine, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Kira
authors.initials: K
authors.lastname: Meyerovich
authors.affiliation: ULB Center for Diabetes Research, Faculté de Médecine, Université Libre de Bruxelles (ULB), Brussels, Belgium.
authors.forename: Alessandra K
authors.initials: AK
authors.lastname: Cardozo
authors.affiliation: Laboratoire de Pharmacodynamie et de Thérapeutique, Bâtiment GE, Faculté de Médecine, Université Libre de Bruxelles (ULB), route de Lennik 808, B-1070, Bruxelles, Belgium. herchu@ulb.ac.be.
authors.forename: André
authors.initials: A
authors.lastname: Herchuelz
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000201:enzymology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D019831:Sodium-Calcium Exchanger / Q000235:genetics
chemical_list: D007328:Insulin; C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D053499:Plasma Membrane Calcium-Transporting ATPases; C506959:Atp2b2 protein, mouse; D005947:Glucose
keywords: Beta cell; Calcium; Diabetes; Plasma membrane Ca2+-ATPase; Sodium/calcium exchange