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

Abstract

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 proliferation in 2-year-old mice and that NCX1 inhibition in adult mice by four small molecules of the benzoxyphenyl family stimulates β-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 β-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 β-cell function and proliferation. Specific β-cell inhibition of Na+/Ca2+ exchange by phenoxybenzamyl derivatives may represent an innovative approach to promote β-cell regeneration in diabetes and improve the efficiency of pancreatic islet transplantation for the treatment of the disease.

Emerging diabetes therapies: Bringing back the β-cells

“…Further, heterozygous inactivation of the Na + /Ca 2+ exchanger isoform 1 (NCX1) increased their proliferation in mice [ 113 ]. Based on these findings, the same group found that chemical inhibition of NCX1 had the same effect [ 114 ].…”

Chemical Approaches for Beta-cell Biology

“…200 Based on these observations, recently the same group reported that chemical inhibition of the same target using phenoxybenzamyl-derivatives small molecules promoted beta-cell proliferation in mice. 201 The use of a more stringent approach resulted in the identification of glucocorticoids as inducers of beta-cell proliferation in rats and humans. 202 In this particular instance, beta cells from adult rats and humans were FACS purified and treated with a collection of 1280 bioactive compounds (LOPAC) for 6 days.…”

Advances in Intracellular Calcium Signaling Reveal Untapped Targets for Cancer Therapy

“…Migrating endothelial cells have higher expression of PMCA at their leading edges to maintain low basal [Ca 2+ ]i levels thereby, preventing continued activation of Myosin Light Chain Kinase (MLCK) and extended contraction of the cell membrane at the migration frontier [ 47 ]. On the other hand, NCX1 inhibition and thus impairment of [Ca 2+ ]i extrusion allows the proliferation of pancreatic beta cells [ 48 ].…”