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Extraordinarily Potent Insulinotropin PACAP : Its Characterization as a Pancreatic Peptide and Action Mechanisms in Islet beta-Cells

极其有效的促胰岛素素 PACAP：其作为胰肽的特性及其在胰岛 β 细胞中的作用机制

基本信息

批准号：
06454147
负责人：
YADA Toshihiko
金额：
$ 4.03万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-06454147/
关键词：
PACAP insulin secretion islet autocrine beta-cells PACAP receptor Ca^<2+>受容体サイクリックAMP

项目摘要

Insulin secretion from pancreatic islets is controlled by peptides as well as by nutrients. Two forms of pituitary adenylate cyclase activating polypeptide (PACAP27 and PACAP38) as low as 10^<-13> M stimulated insulin release from rat islets in a glucosedependent manner. PACAP also increased cytosolic Ca^<2+> concentration ( [Ca^<2+>] _i) in islet beta-cells. A blocker of the L-type Ca^<2+> channel abolished both [Ca^<2+>] _i and insulin responses. PACAP stimulated production of cAMP in islets, and a rise in cAMP mimicked PACAP in increasing [Ca^<2+>] _i in beta-cells. Vasoactive intestinal peptide, a peptide exhibiting high amino acid homology with PACAP,also increased [Ca^<2+>] _i in beta-cells but only at concentrations in the nanomolar range, indicating that PACAP27 is 4 logs more potent. High-affinity type-I PACAP receptor was immunohistochemically localized in islets.We next examined the source and physiological role of PACAP in islets. PACAP-immunoreactivity was demonstrated in pancreatic nerve fibers and islets. PACAP mRNA was detected in islets and in the beta-cell line MIN6. Stimulation of insulin release by high glucose from isolated islets was attenuated by a specific PACAP antiserum. The islet incubation medium with high glucose possessed a capacity, which was neutralized by PACAP antiserum, to increase [Ca^<2+>] _i in beta-cells.The results indicate that PACAP reacts with high affinity PACAP-selective receptor and raises cAMP in beta-cells, which in turn enhances the L-type Ca^<2+> channel activity, increases [Ca^<2+>] _i and consequently potentiates glucose-induced insulin release. PACAP is by far the most potent insulinotropic peptide known. Moreover, PACAP is released from islets and acts on islet beta-cells, thus acting as an autocrine hormone. PACAP,via the autocrine action, amplifies glucose-induced insulin secretion in islets, which is characteristically impaired in non-insulin-dependent diabetes mellitus.

胰岛的胰岛素分泌受肽和营养素的控制。两种垂体腺苷酸环化酶激活多肽（PACAP 27和PACAP 38）在低至10 μ <-13>M时以葡萄糖依赖性方式刺激大鼠胰岛释放胰岛素。PACAP还增加胰岛β细胞胞浆Ca^<2+>浓度（[Ca^<2+] _i）。L型Ca^<2+>通道阻断剂可同时阻断[Ca^<2+>] _i和胰岛素反应。PACAP刺激胰岛产生cAMP，cAMP的增加与PACAP增加β细胞[Ca^<2+>] _i相似。血管活性肠肽，一种与PACAP具有高度氨基酸同源性的肽，也增加β细胞中的[Ca^2+] _i，但仅在纳摩尔范围内的浓度下，表明PACAP 27的效力高4个对数。高亲和力的I型PACAP受体在胰岛中被化学定位，我们接下来研究了PACAP在胰岛中的来源和生理作用。PACAP-免疫反应性被证明在胰腺神经纤维和胰岛。在胰岛和β细胞系MIN 6中检测到PACAP mRNA。用特异性PACAP抗血清减弱高糖刺激离体胰岛释放胰岛素的作用。高糖培养液可使β细胞内[Ca^<2+>] i增加，但这种作用可被PACAP抗血清中和，结果表明，PACAP与高亲和力的PACAP选择性受体反应，使β细胞内cAMP升高，进而增强L型Ca^<2+>通道活性，增加[Ca^<2+>] i，从而增强葡萄糖诱导的胰岛素释放。PACAP是迄今为止已知的最有效的促胰岛素肽。此外，PACAP从胰岛释放并作用于胰岛β细胞，从而作为自分泌激素。PACAP通过自分泌作用放大胰岛中葡萄糖诱导的胰岛素分泌，这在非胰岛素依赖型糖尿病中是特征性受损的。