title: Heterozygous inactivation of the Na/Ca exchanger increases glucose-induced insulin release, β-cell proliferation, and mass.
abstract: OBJECTIVE
  We have previously shown that overexpression of the Na-Ca exchanger (NCX1), a protein responsible for Ca(2+) extrusion from cells, increases β-cell programmed cell death (apoptosis) and reduces β-cell proliferation. To further characterize the role of NCX1 in β-cells under in vivo conditions, we developed and characterized mice deficient for NCX1.
  
  
  METHODS
  Biologic and morphologic methods (Ca(2+) imaging, Ca(2+) uptake, glucose metabolism, insulin release, and point counting morphometry) were used to assess β-cell function in vitro. Blood glucose and insulin levels were measured to assess glucose metabolism and insulin sensitivity in vivo. Islets were transplanted under the kidney capsule to assess their performance to revert diabetes in alloxan-diabetic mice.
  
  
  RESULTS
  Heterozygous inactivation of Ncx1 in mice induced an increase in glucose-induced insulin release, with a major enhancement of its first and second phase. This was paralleled by an increase in β-cell proliferation and mass. The mutation also increased β-cell insulin content, proinsulin immunostaining, glucose-induced Ca(2+) uptake, and β-cell resistance to hypoxia. In addition, Ncx1(+/-) islets showed a two- to four-times higher rate of diabetes cure than Ncx1(+/+) islets when transplanted into diabetic animals.
  
  
  CONCLUSIONS
  Downregulation of the Na/Ca exchanger leads to an increase in β-cell function, proliferation, mass, and resistance to physiologic stress, namely to various changes in β-cell function that are opposite to the major abnormalities seen in type 2 diabetes. This provides a unique model for the prevention and treatment of β-cell dysfunction in type 2 diabetes and after islet transplantation.
authors.affiliation: Laboratory of Pharmacology, Université Libre de Bruxelles, Faculté de Médecine, Brussels, Belgium.
authors.forename: Evrard
authors.initials: E
authors.lastname: Nguidjoe
authors.forename: Sophie
authors.initials: S
authors.lastname: Sokolow
authors.forename: Serge
authors.initials: S
authors.lastname: Bigabwa
authors.forename: Nathalie
authors.initials: N
authors.lastname: Pachera
authors.forename: Eva
authors.initials: E
authors.lastname: D'Amico
authors.forename: Florent
authors.initials: F
authors.lastname: Allagnat
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Vanderwinden
authors.forename: Abdullah
authors.initials: A
authors.lastname: Sener
authors.forename: Mario
authors.initials: M
authors.lastname: Manto
authors.forename: Marianne
authors.initials: M
authors.lastname: Depreter
authors.forename: Jan
authors.initials: J
authors.lastname: Mast
authors.forename: Geraldine
authors.initials: G
authors.lastname: Joanny
authors.forename: Eduard
authors.initials: E
authors.lastname: Montanya
authors.forename: Jacques
authors.initials: J
authors.lastname: Rahier
authors.forename: Alessandra K
authors.initials: AK
authors.lastname: Cardozo
authors.forename: Décio L
authors.initials: DL
authors.lastname: Eizirik
authors.forename: Stéphane
authors.initials: S
authors.lastname: Schurmans
authors.forename: André
authors.initials: A
authors.lastname: Herchuelz
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D005947:Glucose; D002118:Calcium