Islet β cell expression of constitutively active Akt1/PKBα induces striking hypertrophy, hyperplasia, and hyperinsulinemia
Islet β cell expression of constitutively active Akt1/PKBα induces striking hypertrophy, hyperplasia, and hyperinsulinemia
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DOI：
10.1172/jci13785
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发表时间：
2001-12-01
影响因子：
15.9
通讯作者：
Permutt, MA
中科院分区：
文献类型：
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作者：
Bernal-Mizrachi, E;Wen, W;Permutt, MA
磷酸肌醇3-激酶-Akt/PKB通路介导培养细胞中各种营养物质和生长因子的促有丝分裂作用。为了研究其在胰岛β细胞中的体内作用，我们创建了表达与胰岛素基因启动子连接的组成型活性Akt 1/PKB α的转基因小鼠。转基因小鼠表现出明显可见的胰岛质量增加，主要是由于含胰岛素的β细胞增殖。形态测定分析证实，与野生型小鼠相比，转基因小鼠在5周时β细胞质量/胰腺增加6倍，5-溴-2 '-脱氧尿苷掺入增加2倍，每个胰腺区域β细胞数量增加4倍，细胞大小增加2倍。至少部分β细胞数量的增加可以通过新生来解释，新生通过包括从小管上皮增殖的β细胞的标准来定义，并且通过分散在转基因小鼠的整个外分泌胰腺中的单个和双联体β细胞的数量增加六倍来解释。与野生型小鼠相比，葡萄糖耐量得到改善，空腹和餐后胰岛素摄入量更大。葡萄糖刺激的胰岛素分泌维持在转基因小鼠，这是抵抗链脲佐菌素诱导的糖尿病。我们的结论是Akt 1/PKB α通路的激活通过改变胰岛β细胞的大小和数量来影响胰岛β细胞的质量。
The phosphoinositide 3-kinase-Akt/PKB pathway mediates the mitogenic effects various nutrients and growth factors in cultured cells. To study its effects in vivo in pancreatic islet beta cells, we created transgenic mice that expressed a constitutively active Akt1/PKB alpha linked to an Insulin gene promoter. Transgenic mice exhibited a grossly visible increase in islet mass, largely due to proliferation of insulin-containing beta cells. Morphometric analysis verified a six-fold increase in beta cell mass/pancreas, a two-fold increase in 5-bromo-2'-deoxyuridine incorporation, a four-fold increase in the number of beta cells per pancreas area, and a two-fold increase in cell size in transgenic compared with wildtype mice at 5 weeks. At least part of the increase in beta cell number may be accounted for by neogenesis, defined by criteria that include beta cells proliferating from ductular epithelium, and by a six-fold increase in the number of single and doublet beta cells scattered throughout the exocrine pancreas of the transgenic mice. Glucose tolerance was improved, and fasting as well as fed insulin was greater compared with wild-type mice. Glucose-stimulated insulin secretion was maintained in transgenic mice, which were resistant to streptozotocin-induced diabetes. We conclude that activation of the Akt1/PKB alpha pathway affects islet beta cell mass by alteration of size and number.