Laboratory of Molecular Endocrinology, Massachusetts General Hospital, Boston, MA 02114, USA.
Adv Exp Med Biol. 2010;654:391-419. doi: 10.1007/978-90-481-3271-3_17.
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.
Wnt 信号通路不仅对干细胞的扩增、分化和迁移至关重要,而且对器官发生和身体形态的发育也很重要。β-连环蛋白/TCF7L2 依赖性 Wnt 信号(经典途径)参与胰腺发育、胰岛功能以及胰岛素的产生和分泌。肠促胰岛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,这对于其有丝分裂和细胞保护作用是必需的。全基因组关联研究揭示了 19 个基因座,这些基因座赋予了 2 型糖尿病发展的易感性。其中至少有 14 个糖尿病风险等位基因编码的蛋白质与胰岛生长和功能有关。其中 7 个是 Wnt 信号的组成部分或已知的靶基因。转录因子 TCF7L2 与糖尿病风险的相关性特别强,似乎在经典 Wnt 信号和β细胞功能中都具有重要作用。在胰岛中实验性地丧失 TCF7L2 功能以及人类 TCF7L2 等位基因中的多态性会损害葡萄糖刺激的胰岛素分泌,这表明 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很大影响。这篇综述重点讨论了激素对胰岛中 Wnt 信号的调节以及 Wnt 信号通路成分突变作为 2 型糖尿病风险相关等位基因来源的意义。