Abstract
The effect of the novel imidazoline compound 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-(5-methyl-2,3-dihydrobenzofuran-7-yl)-ethyl]-pyridine (NNC77-0020) on stimulus-secretion coupling and hormone secretion was investigated in mouse pancreatic islets and isolated α- and β-cells. In the presence of elevated glucose concentrations NNC77-0020 stimulated insulin secretion concentration dependently (EC50 64 nM) by 200% without affecting the whole-cell K+ current or cytoplasmic Ca2+ levels. Capacitance measurements in single mouse β-cells showed that intracellular application of NNC77-0020 via the recording pipette enhanced Ca2+-dependent exocytosis. This action was dependent on protein kinase C (PKC) and cytoplasmic phospholipase A2 (cPLA2) activity and required functional granular ClC-3 Cl− channels. In intact islets NNC77-0020 stimulated glucose-dependent somatostatin secretion, an effect that was also dependent on PKC and cPLA2 activity. NNC77-0020 also inhibited glucagon secretion. In single mouse α-cells this action was not associated with a change in spontaneous electrical activity and resulted from a reduction in the rate of Ca2+-dependent exocytosis. Inhibition of exocytosis by NNC77-0020 was pertussis toxin sensitive and mediated by activation of the protein phosphatase calcineurin. In conclusion, our data suggest that the imidazoline compound NNC77-0020 modulates pancreatic hormone secretion in a complex fashion, comprising glucose-dependent stimulation of insulin and somatostatin secretion and inhibition of glucagon release. These mechanisms of action constitute an ideal basis for the development of novel imidazoline-containing anti-diabetic compounds.
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Acknowledgements
We thank Tina Olsen and Berit Gerlach for technical assistance. MH holds a scholarship from the Academy of Technical Sciences and Novo Nordisk, Denmark. HLO holds a scholarship from the Medicon Valley Academy and Novo Nordisk, Denmark
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Høy, M., Olsen, H.L., Bokvist, K. et al. The imidazoline NNC77-0020 affects glucose-dependent insulin, glucagon and somatostatin secretion in mouse pancreatic islets. Naunyn-Schmiedeberg's Arch Pharmacol 368, 284–293 (2003). https://doi.org/10.1007/s00210-003-0797-1
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DOI: https://doi.org/10.1007/s00210-003-0797-1