Pancreas-specific Gsalpha deficiency has divergent effects on pancreatic alpha- and beta-cell proliferation.
Pancreas-specific Gsalpha deficiency has divergent effects on pancreatic alpha- and beta-cell proliferation.
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DOI：
10.1677/joe-10-0030
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Weinstein LS
中科院分区：
文献类型：
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作者：
Xie T;Chen M;Weinstein LS
在胰岛细胞中，普遍表达的G蛋白α-亚基Gsα介导细胞内cAMP对胰高血糖素样肽1 （glucagon-like peptide 1, GLP1）和其他肠促胰岛素激素的反应。我们之前的研究表明，β细胞特异性Gsα缺乏症（β gsko）小鼠会发展为严重的早发性胰岛素缺乏性糖尿病，并伴有β细胞增殖严重缺陷。我们现在通过将Gsα-floxed小鼠与Pdx1-cre转基因小鼠（PGsKO）配对，产生了整个胰腺的Gsα缺乏症小鼠。PGsKO小鼠在年轻时也发生了严重的胰岛素缺乏性糖尿病，证实了Gsα信号在β细胞生长和功能中的重要作用。与βGsKO小鼠不同，PGsKO小鼠的胰岛有相对较大比例的α细胞分布在整个胰岛内部。使用神经原素3启动子-cre重组酶转基因小鼠系，在胰岛细胞特异性Gsα缺乏小鼠中观察到类似的结果。对a细胞系αTC1的研究证实，cAMP信号的减少会增加细胞的增殖，而cAMP的增加则会产生相反的效果。因此，Gsα/cAMP信号通路对胰腺α和β细胞增殖具有相反的作用，而通过Gsα信号通路破坏α和β细胞中GLP1的作用可能是2型糖尿病患者观察到的胰岛素和胰高血糖素相互作用的重要因素。此外，PGsKO在外分泌胰腺中表现出形态变化和营养不良和脱水的证据，表明Gsα在外分泌胰腺中也起重要作用。
The ubiquitously expressed G protein α-subunit Gsα mediates the intracellular cAMP response to glucagon-like peptide 1 (GLP1) and other incretin hormones in pancreatic islet cells. We have shown previously that mice with β cell-specific Gsα deficiency (βGsKO) develop severe early-onset insulin-deficient diabetes with a severe defect in β cell proliferation. We have now generated mice with Gsα deficiency throughout the whole pancreas by mating Gsα-floxed mice with Pdx1-cre transgenic mice (PGsKO). PGsKO mice also developed severe insulin-deficient diabetes at a young age, confirming the important role of Gsα signaling in β cell growth and function. Unlike in βGsKO mice, islets in PGsKO mice had a relatively greater proportion of α cells which were spread throughout the interior of the islet. Similar findings were observed in mice with pancreatic islet cell-specific Gsα deficiency using a neurogenin 3 promoter-cre recombinase transgenic mouse line. Studies in the a cell line αTC1 confirmed that reduced cAMP signaling increased cell proliferation while increasing cAMP produced the opposite effect. Therefore it appears that Gsα/cAMP signaling has opposite effects on pancreatic α and β cell proliferation, and that impaired GLP1 action in α and β cells via Gsα signaling may be an important contributor to the reciprocal effects on insulin and glucagon observed in type 2 diabetics. In addition, PGsKO show morphological changes in exocrine pancreas and evidence for malnutrition and dehydration, indicating an important role for Gsα in the exocrine pancreas as well.