Heterozygous inactivation of plasma membrane Ca(2+)-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability

Pachera, Nathalie;Papin, Julien;Zummo, Francesco P;Rahier, Jacques;Herchuelz, André;et.al.
(2015) Diabetologia : clinical and experimental diabetes and metabolism — Vol. 58, n° 12, p. 2843-2850 (2015)

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Authors
  • Pachera, Nathalie
    Author
  • Papin, Julien
    Author
  • Zummo, Francesco P
    Author
  • Rahier, JacquesUCLouvain
    Author
  • Herchuelz, André
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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 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/INTERPRETATION: 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.
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Pachera, N., Papin, J., Zummo, F. P., Rahier, J., Mast, J., Meyerovich, K., Cardozo, A. K., & Herchuelz, A. (2015). Heterozygous inactivation of plasma membrane Ca(2+)-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability. Diabetologia : clinical and experimental diabetes and metabolism, 58(12), 2843-2850. https://doi.org/10.1007/s00125-015-3745-y (Original work published 2015)