Glucose Effects on Beta-Cell Growth and Survival Require Activation of Insulin Receptors and Insulin Receptor Substrate 2
Glucose Effects on Beta-Cell Growth and Survival Require Activation of Insulin Receptors and Insulin Receptor Substrate 2
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DOI：
10.1128/mcb.01489-08
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发表时间：
2009-06-01
影响因子：
5.3
通讯作者：
Kulkarni, Rohit N.
中科院分区：
文献类型：
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作者：
Assmann, Anke;Ueki, Kohjiro;Kulkarni, Rohit N.
胰岛素和胰岛素样生长因子I （IGF-I）是普遍存在的激素，调节大多数哺乳动物细胞的生长和代谢，包括胰腺细胞。除了作为胰岛素分泌剂，葡萄糖还调节β细胞的增殖和存活。然而，目前尚不清楚葡萄糖的后一种效应是否继发于分泌的胰岛素对胰岛素信号蛋白的自分泌激活。为了检验这种可能性，我们研究了外源性葡萄糖或胰岛素对完全缺乏胰岛素受体（β IRKO）或胰岛素受体底物2 （β IRS2KO）的β细胞系的影响。在控制β细胞系中，外源性添加胰岛素或葡萄糖激活胰岛素信号通路中的蛋白，胰岛素比葡萄糖更早达到峰值。胰岛素刺激β IRKO和β IRS2KO细胞导致磷脂酰肌醇3-激酶和Akt激酶的激活钝化，而令人惊讶的是，葡萄糖未能激活任何一种激酶，但磷酸化了细胞外信号调节激酶。对照β细胞表现出IGF-1受体的低表达，与β IRKO细胞的代偿性上调相比。信号数据支持β IRKO和β IRS2KO细胞在葡萄糖刺激下生长缓慢，DNA和蛋白质合成减少。总之，这些研究提供了令人信服的证据，证明葡萄糖对β细胞的生长和存活影响需要激活胰岛素信号通路中的蛋白质。
Insulin and insulin-like growth factor I (IGF-I) are ubiquitous hormones that regulate growth and metabolism of most mammalian cells, including pancreatic beta-cells. In addition to being an insulin secretagogue, glucose regulates proliferation and survival of beta-cells. However, it is unclear whether the latter effects of glucose occur secondary to autocrine activation of insulin signaling proteins by secreted insulin. To examine this possibility we studied the effects of exogenous glucose or insulin in beta-cell lines completely lacking either insulin receptors (beta IRKO) or insulin receptor substrate 2 (beta IRS2KO). Exogenous addition of either insulin or glucose activated proteins in the insulin signaling pathway in control beta-cell lines with the effects of insulin peaking earlier than glucose. Insulin stimulation of beta IRKO and beta IRS2KO cells led to blunted activation of phosphatidylinositol 3-kinase and Akt kinase, while surprisingly, glucose failed to activate either kinase but phosphorylated extracellular signal-regulated kinase. Control beta-cells exhibited low expression of IGF-1 receptors compared to compensatory upregulation in beta IRKO cells. The signaling data support the slow growth and reduced DNA and protein synthesis in beta IRKO and beta IRS2KO cells in response to glucose stimulation. Together, these studies provide compelling evidence that the growth and survival effects of glucose on beta-cells require activation of proteins in the insulin signaling pathway.