Department of Physiology and Center for Integrative Genomics, University of Lausanne, Génopode Building, CH-1015 Lausanne, Switzerland.
Islets. 2009 Nov-Dec;1(3):280-2. doi: 10.4161/isl.1.3.9932.
GLP-1 protects β-cells against apoptosis by still incompletely understood mechanisms. In a recent study, we searched for novel anti-apoptotic pathways by performing comparative transcriptomic analysis of islets from Gipr-/-;Glp-1r-/- mice, which show increased susceptibility to cytokine-induced apoptosis. We observed a strong reduction in IGF-1R expression in the knockout islets suggesting a link between the gluco-incretin and IGF-1R signaling pathways. Using MIN6 and primary islet cells, we demonstrated that GLP-1 strongly stimulates IGF-1R expression and that activation of the IGF-1R/Akt signaling pathway required active secretion of IGF-2 by the β-cells. We showed that inactivation of the IGF-1 receptor gene in β-cells or preventing its up-regulation by GLP-1, as well as suppressing IGF-2 expression or action, blocked the protective effect of GLP-1 against cytokine-induced apoptosis. Thus, an IGF-2/IGF-1 receptor autocrine loop operates in β-cells and GLP-1 increases its activity by enhancing IGF-1R expression and by stimulating IGF-2 secretion. This mechanism is required for GLP-1 to protect β-cells against apoptosis.
GLP-1 通过尚未完全了解的机制保护β细胞免受细胞凋亡。在最近的一项研究中，我们通过对 Gipr-/-;Glp-1r-/- 小鼠胰岛进行比较转录组分析，寻找新的抗细胞凋亡途径，这些小鼠对细胞因子诱导的细胞凋亡更敏感。我们观察到敲除胰岛中 IGF-1R 表达明显减少，表明葡萄糖肠促胰岛素和 IGF-1R 信号通路之间存在联系。使用 MIN6 和原代胰岛细胞，我们证明 GLP-1 可强烈刺激 IGF-1R 表达，而 IGF-1R/Akt 信号通路的激活需要β细胞中 IGF-2 的主动分泌。我们表明，β细胞中 IGF-1 受体基因失活或阻止 GLP-1 上调其表达，以及抑制 IGF-2 的表达或作用，均可阻断 GLP-1 对细胞因子诱导的细胞凋亡的保护作用。因此，IGF-2/IGF-1 受体自分泌环在β细胞中起作用，GLP-1 通过增强 IGF-1R 表达和刺激 IGF-2 分泌来增加其活性。这种机制是 GLP-1 保护β细胞免受细胞凋亡所必需的。
