Na/Ca Exchanger a Druggable Target to Promote -Cell Proliferation and Function.

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/Ca exchanger (isoform 1; NCX1), a protein responsible for Ca extrusion from cells, increases -cell proliferation, mass, and function in mice. Here, we show that 1 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 and . 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 and 1, and inactivates/downregulates the tumor suppressors retinoblastoma protein (pRb) and miR-193a and the cell cycle inhibitor p53. Our data show that Na/Ca exchange is a druggable target to stimulate -cell function and proliferation. Specific -cell inhibition of Na/Ca 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.