Wnt Signaling in Pancreatic Islets
Wnt Signaling in Pancreatic Islets
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DOI：
10.1007/978-90-481-3271-3_17
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发表时间：
2010-01-01
期刊：
影响因子：
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通讯作者：
Habener, Joel F.
中科院分区：
文献类型：
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作者：
Liu, Zhengyu;Habener, Joel F.
Wnt信号通路不仅对干细胞扩增、分化和迁移至关重要，而且对器官发生和身体发育也很重要。β-连环蛋白/TCF 7 L2依赖性Wnt信号传导（经典途径）参与胰腺发育、胰岛功能以及胰岛素产生和分泌。葡萄糖肠降血糖素激素胰高血糖素样肽-1和趋化因子基质细胞衍生因子-1调节β细胞中的经典Wnt信号传导，这对于它们的促有丝分裂和细胞保护作用是必需的。全基因组关联研究发现了19个基因位点，赋予2型糖尿病的发展易感性。这些糖尿病风险等位基因中至少有14个编码与胰岛生长和功能有关的蛋白质。其中7个是Wnt信号传导的组分或已知的靶基因。转录因子TCF 7 L2与糖尿病风险密切相关，并且似乎在经典Wnt信号传导和β细胞功能中具有根本重要性。实验性胰岛TCF 7 L2功能丧失和人类TCF 7 L2等位基因多态性损害葡萄糖刺激的胰岛素分泌，表明Wnt信号通路的扰动可能对2型糖尿病的易感性和发病机制有重大贡献。这篇综述主要关注胰岛中Wnt信号传导的激素调节，以及作为2型糖尿病风险相关等位基因来源的Wnt信号传导途径组分突变的影响。
The Wnt signaling pathway is critically important not only for stem cell amplification, differentiation, and migration, but also is important for organogenesis and the development of the body plan. Beta-catenin/TCF7L2-dependent Wnt signaling (the canonical pathway) is involved in pancreas development, islet function, and insulin production and secretion. The glucoincretin hormone glucagon-like peptide-1 and the chemokine stromal cell-derived factor-1 modulate canonical Wnt signaling in beta-cells which is obligatory for their mitogenic and cytoprotective actions. Genome-wide association studies have uncovered 19 gene loci that confer susceptibility for the development of type 2 diabetes. At least 14 of these diabetes risk alleles encode proteins that are implicated in islet growth and functioning. Seven of them are either components of, or known target genes for, Wnt signaling. The transcription factor TCF7L2 is particularly strongly associated with risk for diabetes and appears to be fundamentally important in both canonical Wnt signaling and beta-cell functioning. Experimental loss of TCF7L2 function in islets and polymorphisms in TCF7L2 alleles in humans impair glucose-stimulated insulin secretion, suggesting that perturbations in the Wnt signaling pathway may contribute substantially to the susceptibility for, and pathogenesis of, type 2 diabetes. This review focuses on considerations of the hormonal regulation of Wnt signaling in islets and implications for mutations in components of the Wnt signaling pathway as a source for risk-associated alleles for type 2 diabetes.