Nguidjoe, Evrard
Sokolow, Sophie
Bigabwa, Serge
Pachera, Nathalie
D'Amico, Eva
Allagnat, Florent
Vanderwinden, Jean-Marie
Sener, Abdullah
Manto, Mario
Depreter, Marianne
Mast, Jan
Joanny, Geraldine
Montanya, Eduard
Rahier, Jacques
[UCL]
Cardozo, Alessandra K.
Eizirik, Décio L.
Schurmans, Stéphane
Herchuelz, André
OBJECTIVE - We have previously shown that overexpression of the Na-Ca exchanger (NCX1), a protein responsible for Ca2+ 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. RESEARCH DESIGN AND METHODS - Biologic and morphologic methods (Ca2+ imaging, Ca2+ 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 Ca2+ uptake, and b-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. © 2011 by the American Diabetes Association.
Bibliographic reference |
Nguidjoe, Evrard ; Sokolow, Sophie ; Bigabwa, Serge ; Pachera, Nathalie ; D'Amico, Eva ; et. al. Heterozygous inactivation of the Na/Ca exchanger increases glucose-induced insulin release, β-cell proliferation, and mass. In: Diabetes, Vol. 60, no. 8, p. 2076-2085 (2011) |
Permanent URL |
http://hdl.handle.net/2078.1/163523 |