β‐Cell Biology of Insulin Secretion

Wollheim, Claes B.; Maechler, Pierre

doi:10.1002/0470862092.d0204

Cited by 2 publications

(2 citation statements)

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“…Calcium is an important signalling molecule involved in key cellular functions such as hormone secretion and cell metabolism, division and death. When stimulated by glucose, beta cells display a complex series of events including the opening of voltagesensitive Ca 2+ channels, leading to Ca 2+ entry into the cell with a subsequent rise in cytosolic free Ca 2+ concentration ([Ca 2+ ] i ) which triggers insulin release [2]. After entering the cell, the ion must be extruded in order to avoid its excessive accumulation, which may be toxic for the cell [3].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

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Heterozygous inactivation of plasma membrane Ca2+-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability

et al. 2015

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Aims/hypothesis 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. Methods 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. Results 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. Conclusions/interpretation 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.

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Section: Electronic Supplementary Materialsmentioning

confidence: 99%

“…To stimulate insulin release, glucose must be metabolised by the pancreatic beta cell [2,28]. As seen in ESM Fig.…”

Section: +/− Islets (Batches Of Ten Islets Four and Five Individual mentioning

confidence: 99%

Heterozygous inactivation of plasma membrane Ca2+-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability

et al. 2015

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

Papin

Zummo

Pachera

et al. 2018

Journal of the Endocrine Society

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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.

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β‐Cell Biology of Insulin Secretion

Cited by 2 publications

References 160 publications

Heterozygous inactivation of plasma membrane Ca2+-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability

Heterozygous inactivation of plasma membrane Ca2+-ATPase in mice increases glucose-induced insulin release and beta cell proliferation, mass and viability

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

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