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01.12.2015 | Article

Heterozygous inactivation of plasma membrane Ca²⁺-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability

verfasst von: Nathalie Pachera, Julien Papin, Francesco P. Zummo, Jacques Rahier, Jan Mast, Kira Meyerovich, Alessandra K. Cardozo, André Herchuelz

Erschienen in: Diabetologia | Ausgabe 12/2015

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Abstract

Aims/hypothesis

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 Ca²⁺ extrusion—the Na/Ca exchanger (NCX) and the plasma membrane Ca²⁺-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 (Ca²⁺ imaging, Ca²⁺ 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 Ca²⁺ 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/interpretation

The present data indicates that inhibition of Ca²⁺ 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 Ca²⁺ extrusion mechanisms by small molecules in beta cells may represent a new approach in the treatment of type 1 and type 2 diabetes.

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Titel: Heterozygous inactivation of plasma membrane Ca2+-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability
verfasst von: Nathalie Pachera
Julien Papin
Francesco P. Zummo
Jacques Rahier
Jan Mast
Kira Meyerovich
Alessandra K. Cardozo
André Herchuelz
Publikationsdatum: 01.12.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 12/2015
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-015-3745-y

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Heterozygous inactivation of plasma membrane Ca²⁺-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability