Background The divalent cation Calcium (Ca 2+ ) regulates a wide range of processes in disparate cell types. Within insulin-producing β-cells, increases in cytosolic Ca 2+ directly stimulate insulin vesicle exocytosis, but also initiate multiple signaling pathways. Mediated through activation of downstream kinases and transcription factors, Ca 2+ -regulated signaling pathways leverage substantial influence on a number of critical cellular processes within the β-cell. Additionally, there is evidence that prolonged activation of these same pathways is detrimental to β-cell health and may contribute to Type 2 Diabetes pathogenesis. Scope of review This review aims to briefly highlight canonical Ca 2+ signaling pathways in β-cells and how β-cells regulate the movement of Ca 2+ across numerous organelles and microdomains. As a main focus, this review synthesizes experimental data from in vitro and in vivo models on both the beneficial and detrimental effects of Ca 2+ signaling pathways for β-cell function and health. Major conclusions Acute increases in intracellular Ca 2+ stimulate a number of signaling cascades, resulting in (de-)phosphorylation events and activation of downstream transcription factors. The short-term stimulation of these Ca 2+ signaling pathways promotes numerous cellular processes critical to β-cell function, including increased viability, replication, and insulin production and secretion. Conversely, chronic stimulation of Ca 2+ signaling pathways increases β-cell ER stress and results in the loss of β-cell differentiation status. Together, decades of study demonstrate that Ca 2+ movement is tightly regulated within the β-cell, which is at least partially due to its dual roles as a potent signaling molecule.

Cytosolic calcium influx activates signaling pathways known to support pancreatic beta cell function and survival by modulating gene expression. Impaired calcium signaling leads to decreased beta cell mass and diabetes. To appreciate the causes of these cytotoxic perturbations, a more detailed understanding of the relevant signaling pathways and their respective gene targets is required. In this study, we examined the calcium-induced expression of the cytoprotective beta cell transcription factor Npas4. Pharmacological inhibition implicated the calcineurin, Akt/protein kinase B, and Ca 2؉ / calmodulin-dependent protein kinase signaling pathways in the regulation of Npas4 transcription and translation. Both Npas4 mRNA and protein had high turnover rates, and, at the protein level, degradation was mediated via the ubiquitinproteasome pathway. Finally, beta cell cytotoxicity of the calcineurin inhibitor and immunosuppressant tacrolimus (FK-506) was prevented by Npas4 overexpression. These results delineate the pathways regulating Npas4 expression and stability and demonstrate its importance in clinical settings such as islet transplantation.Pancreatic beta cells are critical for the regulation of systemic glycemia because of their ability to sense ambient glucose levels and release the glucose-lowering hormone insulin. The triggering phase of insulin secretion involves glucose uptake into the cell via GLUT1/2, phosphorylation by glucokinase, and metabolism into ATP. This results in the closure of the ATP-sensitive potassium channel, followed by membrane depolarization, calcium influx through L-type voltage-dependent calcium channels and exocytosis of insulin granules (1, 2).In addition to the direct stimulation of insulin secretion, calcium influx also triggers a number of calcium-dependent signaling pathways that promote beta cell function and survival ( Fig. 2A) (3-13). Downstream of these signaling pathways, activation of transcription factors of the CREB, 4 forkhead box protein O (FOXO), and NFAT families mediates gene expression. CREB mediates anti-apoptotic effects in beta cells involving the action of insulin (14) or the incretin hormones (e.g. gastric inhibitory polypeptide and glucagon-like peptide 1) (15, 16), whereas FOXO1 prevents stress-induced beta cell dedifferentiation (17) and reduces glucose-induced oxidative stress (18).In further support of the functional importance of calcium signaling pathways in beta cells, knock out of the regulatory subunit calcineurin b1 of the phosphatase CaN resulted in hypoinsulinemia and hyperglycemia because of reduced beta cell proliferation and mass in aged mice (5). Conditional expression of active NFATc1 (which localizes to the nucleus independently of CaN) rescued the knockout phenotype.The importance of calcineurin activity within human ␤ cells has also been demonstrated during transplantation. Use of the CaN inhibitor tacrolimus (FK-506) as an immunosuppressant results in early graft failure of human islets transplanted into diabetic mice (19), causes beta cell...

The high-mobility group box transcription factor SOX4 is the most highly expressed SOX family protein in pancreatic islets, and mutations in are associated with an increased risk of developing type 2 diabetes. We used an inducible β-cell knockout mouse model to test the hypothesis that is essential for the maintenance of β-cell number during the development of type 2 diabetes. Knockout of at 6 weeks of age resulted in time-dependent worsening of glucose tolerance, impairment of insulin secretion, and diabetes by 30 weeks of age. Immunostaining revealed a decrease in β-cell mass in knockout mice that was caused by a 39% reduction in β-cell proliferation. Gene expression studies revealed that induction of the cell cycle inhibitor was responsible for the decreased proliferation in the knockout animals. Altogether, this study demonstrates that SOX4 is necessary for adult β-cell replication through direct regulation of the β-cell cycle.