INHIBITORY EFFECT OF ODN, A NATURALLY-OCCURRING PROCESSING PRODUCT OF DIAZEPAM-BINDING INHIBITOR, ON SECRETAGOGUES-INDUCED INSULIN-SECRETION
INHIBITORY EFFECT OF ODN, A NATURALLY-OCCURRING PROCESSING PRODUCT OF DIAZEPAM-BINDING INHIBITOR, ON SECRETAGOGUES-INDUCED INSULIN-SECRETION
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DOI：
10.1016/0167-0115(95)00002-s
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发表时间：
1995-04-14
影响因子：
--
通讯作者：
GUIDOTTI, A
中科院分区：
文献类型：
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作者：
DESTEFANIS, P;IMPAGNATIELLO, F;GUIDOTTI, A
地西泮结合抑制剂（DBI 1 -86）是一种肽，其大量存在于肠和胰腺中，并且以低纳摩尔浓度抑制葡萄糖刺激的胰岛素从灌注的胰腺和分离的胰岛释放。在此，DBI 33 -50（也称为ODN，十八碳神经肽）（DBI 1 -86的天然加工产物之一）和某些合成修饰衍生物已显示可抑制葡萄糖和格列本脲刺激的离体大鼠胰岛胰岛素分泌以及格列本脲刺激的仓鼠胰岛素瘤（HIT-T15）β细胞系胰岛素分泌。DBI 17 -50（TTN; triakontatetraneuropeptide）是DBI的另一种主要加工产品，但没有影响。ODN对由8.3或16.7 mM葡萄糖诱导的胰岛素分泌的影响的50%抑制浓度（IC 50）大致相同：5至6 nM。此外，ODN抑制0.01或1 μ M格列本脲诱导的胰岛素释放，在分离的胰岛和HIT-T15 β细胞中具有相似的IC 50（8 - 10 nM）。在浓度高达1 μ M时，ODN对PACAP（垂体腺苷酸环化酶多肽）、BAYK 8644（甲基-（1，4-二氢-2，6-二甲基-3-硝基-4，2-三氟甲基苯基）吡啶-5-羧酸酯）诱导的胰岛素分泌没有影响，并且仅轻微影响IBMX-（异丁基甲基黄嘌呤）诱导的胰岛素分泌。这表明ODN不直接作用于ATP调节的K+通道、电压依赖性Ca 2+通道或cAMP产生。相反，ODN抑制由硝普钠诱导的胰岛素分泌的方式是独立于细胞外Ca 2+的存在。这些结果表明DBI的ODN或ODN样肽片段可能通过调节细胞质游离Ca 2+浓度的信号通路抑制葡萄糖或格列本脲诱导的胰岛素分泌。
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 or 16.7 mM glucose was approximately the same: 5 to 6 nM. Moreover, ODN inhibited insulin release induced by 0.01 or 1 mu M 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 mu M, 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.