An Imidazoline Compound Completely Counteracts Interleukin-1β toxic Effects to Rat Pancreatic Islet β Cells
In vitro studies have demonstrated that interleukin (IL)-1β decreases insulin and DNA contents in pancreatic islet β cells, causing structural damage, that it is toxic to cultured human islet β cells and that it is able to induce apoptosis in these cells.
Materials and Methods
Isolated rat islets of Langerhans were exposed in vitro to interleukin (IL)-1β and either the imidazoline compound RX871024 (RX) or/and M40403, an Mn-containing superoxide dismutase mimetic (MnSODm).
Insulin secretion, on days 1, 2 and 3 after challenge with 3 ng/ml of IL-1β, was almost abolished and this was accompanied by an early increase in MnSOD activity. By days 2 and 3, SOD activities were lower than those of untreated controls and NO significantly increased by day 2. Moreover, IL-1β induced a significant increase in MnSOD transcripts, while iNOS mRNA appeared by days 2 and 3 when MnSOD mRNA was absent. RX blocked all toxic effects of IL-1β by maintaining insulin secretion and islet β cell phenotype, including the inhibition of nonspecific proteins and of iNOS induction. In contrast, the MnSODm, failed to counteract iNOS induction as well as the reduced insulin secretion.
In summary, our findings stress that IL-1β-induced suppression of insulin secretion may be related to iNOS induction in β cells and that RX can reverse this effect, by maintaining insulin secretion. Oppositely, the MnSODm is not able to restore IL-1β-suppressed insulin secretion. Hence, imidazoline compounds may protect β cells against damage caused by IL-1β-induced free oxygen and nitrogen radicals.
This work was partly supported by the Italian Ministry for University and Research and by the Danish Biotechnology Program.
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