An imidazoline compound completely counteracts interleukin-1[beta] toxic effects to rat pancreatic islet [beta] cells.
BACKGROUND
In vitro studies have demonstrated that interleukin (IL)-1beta decreases insulin and DNA contents in pancreatic islet beta cells, causing structural damage, that it is toxic to cultured human islet beta cells and that it is able to induce apoptosis in these cells.


METHODS
Isolated rat islets of Langerhans were exposed in vitro to interleukin (IL)-1beta and either the imidazoline compound RX871024 (RX) or/and M40403, an Mn-containing superoxide dismutase mimetic (MnSODm).


RESULTS
Insulin secretion, on days 1, 2 and 3 after challenge with 3 ng/ml of IL-1beta, 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-1beta 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-1beta by maintaining insulin secretion and islet beta 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.


CONCLUSIONS
In summary, our findings stress that IL-1beta-induced suppression of insulin secretion may be related to iNOS induction in beta cells and that RX can reverse this effect, by maintaining insulin secretion. Oppositely, the MnSODm is not able to restore IL-1beta-suppressed insulin secretion. Hence, imidazoline compounds may protect beta cells against damage caused by IL-1beta-induced free oxygen and nitrogen radicals.
Papaccio
Gianpaolo
G
Department of Experimental Medicine, Laboratory of Histology and Embryology, School of Medicine, 2nd University of Naples, Italy. gianpaolo.papaccio@unina2.it
Nicoletti
Ferdinando
F
Pisanti
Francesco A
FA
Galdieri
Michela
M
Bendtzen
Klaus
K
D000818:Animals; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008345:Manganese; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009942:Organometallic Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000187:drug effects / Q000235:genetics
C101943:2-(2-imidazolin-2-yl)-1-phenyl-1H-indole; D007093:Imidazoles; D007211:Indoles; D007328:Insulin; D007375:Interleukin-1; D009942:Organometallic Compounds; D012333:RNA, Messenger; C121876:imisopasem manganese; D009569:Nitric Oxide; D008345:Manganese; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D013482:Superoxide Dismutase