Control of pancreatic β-cell fate by insulin signaling
Control of pancreatic β-cell fate by insulin signaling
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DOI：
10.4161/cc.7.10.5865
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发表时间：
2008-05-15
期刊：
影响因子：
4.3
通讯作者：
Alejandro, Emilyn U.
中科院分区：
文献类型：
--
作者：
Johnson, James D.;Alejandro, Emilyn U.
糖尿病是由功能性胰腺β细胞量绝对或相对缺乏引起的。在过去的几年里，人们对胰岛素本身在调节 β 细胞命运中的作用重新产生了兴趣。许多动物模型指出β细胞胰岛素信号传导在胰腺β细胞的存活和增殖中发挥着关键作用。在本文中，我们回顾了一些新的研究，这些研究阐明了胰岛素对 β 细胞发挥抗凋亡和促促分裂作用的机制。我们特别强调 Raf-1 激酶在自分泌胰岛素信号传导和 β 细胞命运决定中的新兴作用。我们还讨论了一些令人兴奋的证据，表明胰岛素剂量与 β 细胞的出生和死亡之间的关系不是线性的。我们基于这些发现提出了一个新的假设，称为“最佳点”假设，它可以解释自分泌/旁分泌胰岛素信号传导正常水平的向上和向下偏差如何在 1 型糖尿病和 2 型糖尿病的发病机制中发挥重要作用。我们还强调了进一步检验这一假设所需的关键实验。
Diabetes results from an absolute or relative deficiency in functional pancreatic beta-cell mass. Over the past few years, there has been renewed interest in the role of insulin itself in the regulation of beta-cell fate. Numerous animal models point to a critical role for beta-cell insulin signaling in the survival and proliferation of pancreatic beta-cells. In the present article, we review new studies that elucidate the mechanism by which insulin exerts anti-apoptotic and promitogenic effects on beta-cells. In particular, we highlight the emerging role for Raf-1 kinase in autocrine insulin signaling and beta-cell fate decisions. We also discuss provocative evidence that the relationship between the dose of insulin and the birth and death of beta-cells is not linear. We propose a new hypothesis based on these findings, called the 'sweet spot' hypothesis, that can explain how both upward and downward deviations from normal levels of autocrine/paracrine insulin signaling might play an important role in the pathogenesis of type 1 diabetes and type 2 diabetes. We also highlight the key experiments that are required to further test this hypothesis.