Dataset Information

Na+/Ca2+ Exchanger a Druggable Target to Promote ?-Cell Proliferation and Function.

ABSTRACT: An important feature of type 2 diabetes is a decrease in ?-cell mass. Therefore, it is essential to find new approaches to stimulate ?-cell proliferation. We have previously shown that heterozygous inactivation of the Na+/Ca2+ exchanger (isoform 1; NCX1), a protein responsible for Ca2+ extrusion from cells, increases ?-cell proliferation, mass, and function in mice. Here, we show that Ncx1 inactivation also increases ?-cell proliferation in 2-year-old mice and that NCX1 inhibition in adult mice by four small molecules of the benzoxyphenyl family stimulates ?-cell proliferation both in vitro and in vivo. NCX1 inhibition by small interfering RNA or small molecules activates the calcineurin/nuclear factor of activated T cells (NFAT) pathway and inhibits apoptosis induced by the immunosuppressors cyclosporine A (CsA) and tacrolimus in insulin-producing cell. Moreover, NCX1 inhibition increases the expression of ?-cell-specific genes, such as Ins1, Ins2, and Pdx1, and inactivates/downregulates the tumor suppressors retinoblastoma protein (pRb) and miR-193a and the cell cycle inhibitor p53. Our data show that Na+/Ca2+ exchange is a druggable target to stimulate ?-cell function and proliferation. Specific ?-cell inhibition of Na+/Ca2+ exchange by phenoxybenzamyl derivatives may represent an innovative approach to promote ?-cell regeneration in diabetes and improve the efficiency of pancreatic islet transplantation for the treatment of the disease.

SUBMITTER: Papin J

PROVIDER: S-EPMC6009611 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Na+/Ca2+ Exchanger a Druggable Target to Promote β-Cell Proliferation and Function.

Papin Julien J Zummo Francesco Paolo FP Pachera Nathalie N Guay Claudiane C Regazzi Romano R Cardozo Alessandra K AK Herchuelz André A

Journal of the Endocrine Society 20180525 7

An important feature of type 2 diabetes is a decrease in β-cell mass. Therefore, it is essential to find new approaches to stimulate β-cell proliferation. We have previously shown that heterozygous inactivation of the Na+/Ca2+ exchanger (isoform 1; NCX1), a protein responsible for Ca2+ extrusion from cells, increases β-cell proliferation, mass, and function in mice. Here, we show that Ncx1 inactivation also increases β-cell prol ...[more]

PMID: 29942927

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Dataset Information

Na+/Ca2+ Exchanger a Druggable Target to Promote ?-Cell Proliferation and Function.

Publications

Na<sup>+</sup>/Ca<sup>2+</sup> Exchanger a Druggable Target to Promote <i>β</i>-Cell Proliferation and Function.

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