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Beta Cell Development and Function Group, Division of Reproduction and Endocrinology, School of Biomedical and Health Sciences, King’s College London, Hodgkin Building HB2.10N, Guy’s Campus, London SE1 9UL, UK
¹ Department of Biological Sciences, Molecular Physiology, Biomedical Research Institute, University of Warwick, Warwick, UK
² Division of Gene and Cell Based Therapy, King’s College London, London, UK

(Requests for offprints should be addressed to P M Jones; Email: peter.jones{at}kcl.ac.uk)

The extracellular calcium-sensing receptor (CaR) is usually associated with systemic Ca²⁺ homeostasis, but the CaR is also expressed in many other tissues, including pancreatic islets of Langerhans. In the present study, we have used human islets and an insulin-secreting cell line (MIN6) to investigate the effects of CaR activation using the calcimimetic R-568, a CaR agonist that activates the CaR at physiological concentrations of extracellular Ca²⁺. CaR activation initiated a marked but transient insulin secretory response from both human islets and MIN6 cells at a sub-stimulatory concentration of glucose, and further enhanced glucose-induced insulin secretion. CaR-induced insulin secretion was reduced by inhibitors of phospholipase C or calcium–calmodulin-dependent kinases, but not by a protein kinase C inhibitor. CaR activation was also associated with an activation of p42/44 mitogen-activated protein kinases (MAPK), and CaR-induced insulin secretion was reduced by an inhibitor of p42/44 MAPK activation. We suggest that the ß-cell CaR is activated by divalent cations co-released with insulin, and that this may be an important mechanism of intra-islet communication between ß-cells.

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