Inhibitory effect of ODN, a naturally occurring processing product of diazepam binding inhibitor, on secretagogues-induced insulin secretion.
Diazepam binding inhibitor (DBI1-86) is a peptide that is present in large amounts in the intestine and pancreas and which inhibits glucose-stimulated insulin release from both perfused pancreas and isolated islets in low nanomolar concentrations. Here, DBI33-50 (also known as ODN, octadecaneuropeptide), one of the naturally occurring processing products of DBI1-86, and certain synthetic modified derivatives, have been shown to inhibit glucose and glibenclamide-stimulated insulin secretion from isolated rat islets and glibenclamide-stimulated insulin secretion from hamster-insulinoma (HIT-T15) beta-cell line. DBI17-50 (TTN; triakontatetraneuropeptide), another prominent processing product of DBI, had no effect. The 50% inhibitory concentration (IC50) for the effect of ODN on insulin secretion induced by 8.3 of 16.7 mM glucose was approximately the same: 5 to 6 nM. Moreover, ODN inhibited insulin release induced by 0.01 or 1 microM glibenclamide with a similar IC50 (8 to 10 nM) in both isolated pancreatic islets and in HIT-T15 beta-cells. At concentration up to 1 microM, ODN had no effect on insulin secretion induced by PACAP (pituitary adenylate cyclase polypeptide), BAYK 8644 (methyl-(1,4-dihydro-2,6-dimethyl-3-nitro-4,2-trifluoromethylphenyl) pyridine-5-carboxylate), and only marginally it affected IBMX-(isobutylmethylxanthine) induced insulin secretion. This indicates that ODN does not act directly on ATP-regulated K+ channels, voltage dependent Ca2+ channels or cAMP production. In contrast, ODN inhibited insulin secretion induced by sodium nitroprussiate in a manner that is independent from the presence of extracellular Ca2+. These results suggest that ODN or ODN-like peptide fragments of DBI, may inhibit glucose or glibenclamide-induced insulin secretion via a signaling pathway that regulate the cytoplasmic free Ca2+ concentration.
De Stefanis
P
P
Nathan S. Kline Institute for Psychiatric Research, Center for Neuropharmacology, Orangeburg, NY 10962, USA.
Impagnatiello
F
F
Berkovich
A
A
Guidotti
A
A
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D026261:Diazepam Binding Inhibitor; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma; D007473:Ion Channels / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010446:Peptide Fragments; D051381:Rats; D013997:Time Factors; D014407:Tumor Cells, Cultured
D026261:Diazepam Binding Inhibitor; D007328:Insulin; D007473:Ion Channels; D009479:Neuropeptides; D010446:Peptide Fragments; C067529:diazepam binding inhibitor (33-50); D009599:Nitroprusside; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000242:Cyclic AMP; D005947:Glucose; D005905:Glyburide; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine