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

Emergent global oscillations in heterogeneous excitable media: The example of pancreatic beta cells

Using the standard van der Pol-FitzHugh-Nagumo excitable medium model I demonstrate a novel generic mechanism, diversity, that provokes the emergence of global oscillations from individually quiescent elements in heterogeneous excitable media. This mechanism may be operating in the mammalian pancreas, where excitable beta cells, quiescent when isolated, are found to oscillate when coupled despite the absence of a pacemaker region.Comment: See home page http://lec.ugr.es/~julya

Anti-diabetic effect of a preparation of vitamins, minerals and trace elements in diabetic rats: a gender difference

BACKGROUND: Although multivitamin products are widely used as dietary supplements to maintain health or as special medical food in certain diseases, the effects of these products were not investigated in diabetes mellitus, a major cardiovascular risk factor. Therefore, here we investigated if a preparation of different minerals, vitamins, and trace elements (MVT) for human use affects the severity of experimental diabetes. METHODS: Two days old neonatal Wistar rats from both genders were injected with 100 mg/kg of streptozotocin or its vehicle to induce diabetes. At week 4, rats were fed with an MVT preparation or vehicle for 8 weeks. Well established diagnostic parameters of diabetes, i.e. fasting blood glucose and oral glucose tolerance test were performed at week 4, 8 and 12. Moreover, serum insulin and blood HbA1c were measured at week 12. RESULTS: An impaired glucose tolerance has been found in streptozotocin-treated rats in both genders at week 4. In males, fasting blood glucose and HbA1c were significantly increased and glucose tolerance and serum insulin was decreased at week 12 in the vehicle-treated diabetic group as compared to the vehicle-treated non-diabetic group. All of the diagnostic parameters of diabetes were significantly improved by MVT treatment in male rats. In females, streptozotocin treatment resulted in a less severe prediabetic-like phenotype as only glucose tolerance and HbA1c were altered by the end of the study in the vehicle-treated diabetic group as compared to the vehicle-treated non-diabetic group. MVT treatment failed to improve the diagnostic parameters of diabetes in female streptozotocin-treated rats. CONCLUSION: This is the first demonstration that MVT significantly attenuates the progression of diabetes in male rats with chronic experimental diabetes. Moreover, we have confirmed that females are less sensitive to STZ-induced diabetes and MVT preparation did not show protection against prediabetic state. This may suggest a gender difference in the pathogenesis of diabetes

Pharmacologie spéciale

SYL-001377 = Volume 1 ;SYL-001378 = Volume 2 ;SYL-001958 = Transparents, Volume 21re édition 1995-1996/11er Doct. Méd. 1re Lic. Sc. Dent.info:eu-repo/semantics/published

Usage et consommation abusive de médicaments dans le traitement de l'obésité

info:eu-repo/semantics/publishe

Bioequivalence assessment and the conduct of bioequivalence trials: a European point of view.

Journal Articleinfo:eu-repo/semantics/publishe

Pharmacologie spéciale

SYL-001379 = Volume 1 ;SYL-001380 = Volume 2 ;SYL-001956 = Transparents, Volume 1 ;SYL-001957 = Transparents, Volume 21re édition 1995-1996/12e grade de Pharmacieninfo:eu-repo/semantics/published

La problématique des essais cliniques: Le point de vue du pharmacologue

info:eu-repo/semantics/publishe