Overexpression of PACAP in transgenic mouse pancreatic beta-cells enhances insulin secretion and ameliorates streptozotocin-induced diabetes.
Overexpression of PACAP in transgenic mouse pancreatic beta-cells enhances insulin secretion and ameliorates streptozotocin-induced diabetes.
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DOI：
10.2337/diabetes.52.5.1155
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发表时间：
2003-05
期刊：
影响因子：
7.7
通讯作者：
Kyohei Yamamoto;H. Hashimoto;S. Tomimoto;N. Shintani;J. Miyazaki;F. Tashiro;H. Aihara;T. Nammo;M. Li;K. Yamagata;J. Miyagawa;Y. Matsuzawa;Yuki Kawabata;Y. Fukuyama;Kazumi Koga;W. Mori;Kazuhiro Tanaka;T. Matsuda;A. Baba
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文献类型：
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作者：
Kyohei Yamamoto;H. Hashimoto;S. Tomimoto;N. Shintani;J. Miyazaki;F. Tashiro;H. Aihara;T. Nammo;M. Li;K. Yamagata;J. Miyagawa;Y. Matsuzawa;Yuki Kawabata;Y. Fukuyama;Kazumi Koga;W. Mori;Kazuhiro Tanaka;T. Matsuda;A. Baba
腺苷酸环化酶激活多肽（PACAP）是血管活性肠肽/胰泌素/胰高血糖素家族的成员，在飞摩尔浓度下以葡萄糖依赖性方式刺激胰岛分泌胰岛素。为了评估PACAP在体内的胰腺功能，我们产生了在人胰岛素启动子控制下胰腺中过表达PACAP的转基因小鼠。北方印迹和免疫组化分析表明，PACAP在胰岛中过表达，特别是在转基因小鼠中。在葡萄糖耐量试验期间，PACAP转基因小鼠和非转基因同窝小鼠之间的血浆葡萄糖和胰高血糖素水平没有差异。然而，转基因小鼠的血浆胰岛素水平在葡萄糖负荷后较高。此外，与非转基因小鼠相比，转基因小鼠中链脲佐菌素诱导的血糖升高减弱。值得注意的是，在链脲佐菌素处理的转基因小鼠中观察到5-溴-2-脱氧尿苷阳性β细胞的增加，但通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记的染色模式没有差异。形态计量学分析显示，总胰岛质量往往增加12个月大的转基因小鼠，但12周龄的转基因和非转基因同窝仔之间没有显着差异。这是首次观察到PACAP在β细胞增殖中发挥重要作用。
Pituitary adenylate cyclase-activating polypeptide (PACAP), a member of the vasoactive intestinal peptide/secretin/glucagon family, stimulates insulin secretion from islets in a glucose-dependent manner at femtomolar concentrations. To assess PACAP's pancreatic function in vivo, we generated transgenic mice overexpressing PACAP in the pancreas under the control of human insulin promoter. Northern blot and immunohistochemical analyses showed that PACAP is overexpressed in pancreatic islets, specifically in transgenic mice. Plasma glucose and glucagon levels during a glucose tolerance test were not different between PACAP transgenic mice and nontransgenic littermates. However, plasma insulin levels in transgenic mice were higher after glucose loading. Also, increases of streptozotocin-induced plasma glucose were attenuated in transgenic compared with nontransgenic mice. Notably, an increase in 5-bromo-2-deoxyuridine-positive beta-cells in the streptozotocin-treated transgenic mice was observed but without differences in the staining patterns by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Morphometric analysis revealed that total islet mass tends to increase in 12-month-old transgenic mice but showed no difference between 12-week-old transgenic and nontransgenic littermates. This is the first time that PACAP has been observed to play an important role in the proliferation of beta-cells.