Na+/Ca(2+ )Exchanger a Druggable Target to Promote beta -Cell Proliferation and Function

An important feature of type 2 diabetes is a decrease in <i>β</i> -cell mass. Therefore, it is essential to find new approaches to stimulate <i>β</i> -cell proliferation. We have previously shown that heterozygous inactivation of the Na <sup>+</sup> /Ca <sup>2+</sup> exchanger (isoform 1; NCX1), a protein responsible for Ca <sup>2+</sup> extrusion from cells, increases <i>β</i> -cell proliferation, mass, and function in mice. Here, we show that <i>Ncx</i> 1 inactivation also increases <i>β</i> -cell proliferation in 2-year-old mice and that NCX1 inhibition in adult mice by four small molecules of the benzoxyphenyl family stimulates <i>β</i> -cell proliferation both <i>in vitro</i> and <i>in vivo</i> . 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 <i>β</i> -cell-specific genes, such as <i>Ins1, Ins2,</i> and <i>Pdx</i> 1, and inactivates/downregulates the tumor suppressors retinoblastoma protein (pRb) and miR-193a and the cell cycle inhibitor p53. Our data show that Na <sup>+</sup> /Ca <sup>2+</sup> exchange is a druggable target to stimulate <i>β</i> -cell function and proliferation. Specific <i>β</i> -cell inhibition of Na <sup>+</sup> /Ca <sup>2+</sup> exchange by phenoxybenzamyl derivatives may represent an innovative approach to promote <i>β</i> -cell regeneration in diabetes and improve the efficiency of pancreatic islet transplantation for the treatment of the disease

Modelling the abdominal wall response under active muscles and effective internal pressures.

Abdominal wall biomechanics is dependent on muscular con-traction and Intra-Abdominal Pressure (IAP) which character-ize different physiological functions and daily tasks. The active behaviour of muscular fibres must be considered within compu-tational models of the abdominal wall. A three dimensional Fi-nite Element (FE) model of a healthy abdomen is developed by implementing different constitutive models to describe the me-chanical behaviour of the different structures. Fascial tissues, aponeuroses and linea alba are modelled as hyperelastic fiber-reinforced materials, while a three-element Hill\u2019s model is as-sumed for the muscles. IAPs are simulated by adopting an in-ternal abdominal cavity. The deformation resulting from different levels of muscle ac-tivation, corresponding to different tasks has been evaluated and the results corresponding to an abdominal crunch are shown. This model represents an advanced approach to simulate abdominal wall mechanics by considering active muscles and effective internal pressures in healthy conditions. The model described in this study can be hence used for a valid clinical support. By means of a similar numerical approach, abdominal pathologies can be properly investigated, such as potential her-niated regions

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

&lt;p&gt;&lt;b&gt;AIMS/HYPOTHESIS: &lt;/b&gt;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.&lt;/p&gt;&lt;p&gt;&lt;b&gt;METHODS: &lt;/b&gt;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.&lt;/p&gt;&lt;p&gt;&lt;b&gt;RESULTS: &lt;/b&gt;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.&lt;/p&gt;&lt;p&gt;&lt;b&gt;CONCLUSIONS/INTERPRETATION: &lt;/b&gt;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.&lt;/p&gt;</p