Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany; Department of Biology, University of Rome Tor Vergata, 00100 Rome, Italy.
Helmholtz Diabetes Center (HMGU) and German Center for Diabetes Research (DZD), 85748 Garching, Munich, Germany.
Cell Metab. 2019 Jun 4;29(6):1422-1432.e3. doi: 10.1016/j.cmet.2019.02.012. Epub 2019 Mar 14.
Progressive decline of pancreatic beta cell function is central to the pathogenesis of type 2 diabetes. Protein phosphorylation regulates glucose-stimulated insulin secretion from beta cells, but how signaling networks are remodeled in diabetic islets in vivo remains unknown. Using high-sensitivity mass spectrometry-based proteomics, we quantified 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls, revealing drastic remodeling of key kinase hubs and signaling pathways. Integration with a literature-derived signaling network implicated GSK3 kinase in the control of the beta cell-specific transcription factor PDX1. Deep phosphoproteomic analysis of human islets chronically treated with high glucose demonstrated a conserved glucotoxicity-dependent role of GSK3 kinase in regulating insulin secretion. Remarkably, the ability of beta cells to secrete insulin in response to glucose was rescued almost completely by pharmacological inhibition of GSK3. Thus, our resource enables investigation of mechanisms and drug targets in type 2 diabetes.
β 细胞功能进行性下降是 2 型糖尿病发病机制的核心。蛋白磷酸化调节β细胞的葡萄糖刺激胰岛素分泌，但在糖尿病胰岛中信号网络如何重塑在体内仍然未知。使用基于高灵敏度质谱的蛋白质组学，我们定量分析了肥胖型糖尿病小鼠和匹配对照胰岛中的 6500 种蛋白质和 13000 种磷酸肽，揭示了关键激酶枢纽和信号通路的剧烈重塑。与文献来源的信号网络整合表明，GSK3 激酶在控制β细胞特异性转录因子 PDX1 的表达中起作用。对长期用高葡萄糖处理的人胰岛进行深度磷酸蛋白质组学分析表明，GSK3 激酶在调节胰岛素分泌方面具有保守的葡萄糖毒性依赖性作用。值得注意的是，β 细胞对葡萄糖分泌胰岛素的能力通过 GSK3 的药理学抑制几乎完全恢复。因此，我们的资源可用于研究 2 型糖尿病的机制和药物靶点。
