Department of Metabolism, Endocrine & Diabetes, University of Michigan, Ann Arbor, MI, USA.
Sci Rep. 2012;2:693. doi: 10.1038/srep00693. Epub 2012 Sep 25.
In settings of increased insulin demand, failure to expand pancreatic β-cells mass leads to diabetes. Genome-wide scans of diabetic populations have uncovered several genes associated with susceptibility to type 2 diabetes and a number of them are part of the Wnt signaling. β-Catenin, a Wnt downstream effector participates in pancreatic development, however, little is known about its action in mature β-cells. Deletion of β-Catenin in Pdx1 pancreatic progenitors leads to a decreased β-cell mass and impaired glucose tolerance. Surprisingly, loss of β-catenin made these mice resistant to high fat diet because of their increased energy expenditure and insulin sensitivity due to hyperactivity. The complexity of this phenotype was also explained in part by ectopic expression of Cre recombinase in the hypothalamus. Our data implicates β-Catenin in the regulation of metabolism and energy homeostasis and suggest that Wnt signaling modulates the susceptibility to diabetes by acting on different tissues.
在胰岛素需求增加的情况下，如果胰腺β细胞的质量不能扩大，就会导致糖尿病。对糖尿病患者的全基因组扫描发现了一些与 2 型糖尿病易感性相关的基因，其中许多基因是 Wnt 信号通路的一部分。β-连环蛋白是 Wnt 的下游效应物，参与了胰腺的发育，但关于其在成熟β细胞中的作用知之甚少。在 Pdx1 胰腺祖细胞中删除 β-连环蛋白会导致β细胞数量减少和葡萄糖耐量受损。令人惊讶的是，由于β-catenin 缺失的小鼠能量消耗和胰岛素敏感性增加（由于过度活跃），它们对高脂肪饮食有抵抗力。由于 Cre 重组酶在下丘脑异位表达，这种表型的复杂性也部分得到了解释。我们的数据表明β-连环蛋白参与了代谢和能量稳态的调节，并表明 Wnt 信号通过作用于不同的组织来调节糖尿病的易感性。
