PKCλ regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic β cells
PKCλ regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic β cells
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DOI：
10.1172/jci200522232
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发表时间：
2005-01-01
影响因子：
15.9
通讯作者：
Kasuga, M
中科院分区：
文献类型：
--
作者：
Hashimoto, N;Kido, Y;Kasuga, M
葡萄糖调节胰岛素分泌的改变是2型糖尿病患者的特征，尽管这种变化的机制尚不清楚。我们现在已经在胰腺β细胞中产生了缺乏PKC的lambda异构体的小鼠（betaPKClambda（-/-）小鼠），并表明这些动物表现出糖耐量受损和低胰岛素血症。此外，从betaPKClambda（-/-）小鼠分离的胰岛中，胰岛素分泌对高浓度葡萄糖的反应受损，而胰岛素释放的基础速率增加。然而，β apkclambda（-/-）小鼠的P细胞质量和胰岛胰岛素含量与对照小鼠没有差异。β apkclambda（-/-）小鼠胰岛中Glut2和hnf3 β mrna丰度降低，受hnf3 β调控的基因表达也受到影响（Sur1和Kir6.2基因表达减少，而己糖激酶1和己糖激酶2基因表达增加）。用腺病毒载体感染betaPKClambda（-/-）小鼠胰岛，使HNF3beta表达正常化，显著逆转了葡萄糖刺激的胰岛素分泌缺陷。这些结果表明，PKClambda通过调节β细胞功能重要基因的表达，在调节葡萄糖诱导的胰岛素分泌中发挥重要作用。
Altered regulation of insulin secretion by glucose is characteristic of individuals with type 2 diabetes mellitus, although the mechanisms that underlie this change remain unclear. We have now generated mice that lack the lambda isoform of PKC in pancreatic beta cells (betaPKClambda(-/-) mice) and show that these animals manifest impaired glucose tolerance and hypoinsulinemia. Furthermore, insulin secretion in response to high concentrations of glucose was impaired, whereas the basal rate of insulin release was increased, in islets isolated from betaPKClambda(-/-) mice. Neither the P cell mass nor the islet insulin content of betaPKClambda(-/-) mice differed from that of control mice, however. The abundance of mRNAs for Glut2 and HNF3beta was reduced in islets of betaPKClambda(-/-) mice, and the expression of genes regulated by HNF3beta was also affected (that of Sur1 and Kir6.2 genes was reduced, whereas that of hexokinase 1 and hexokinase 2 genes was increased). Normalization of HNF3beta expression by infection of islets from betaPKClambda(-/-) mice with an adenoviral vector significantly reversed the defect in glucose-stimulated insulin secretion. These results indicate that PKClambda plays a prominent role in regulation of glucose-induced insulin secretion by modulating the expression of genes important for beta cell function.