胰岛β细胞“不允许基因”与β细胞功能关系的研究进展

摘要

胰岛β细胞是体内唯一一种具有分泌胰岛素功能的细胞.β细胞精确控制胰岛素的分泌,这不仅仅需要细胞特异性的基因表达,而且需要某些基因表达的选择性抑制.胰岛β细胞“不允许基因”是这样一组基因,其表达在胰岛β细胞被高度选择性抑制,以避免干扰β细胞功能.目前已经证实,在胰岛β细胞内多达60个以上的基因被选择性抑制,包括乳酸脱氢酶A基因(Ldha)和单羧酸转运蛋白-1基因(Mct1/Slc16a1)这两个“创始成员”.胰岛β细胞“不允许基因”失活涉及组蛋白修饰和microRNA介导的基因沉默等多种机制.Mct1基因突变导致运动后高胰岛素性低血糖症;2型糖尿病患者和模型小鼠中胰岛β细胞Ldha表达上调.靶向失调胰岛β细胞“不允许基因”可能成为2型糖尿病未来新的治疗手段.%Pancreatic beta cells are the only cell type in the body secreting insulin.Fine regulation of beta-cell function results not only from beta-cell-specific gene expression,but also from beta-cell-selective repression of certain genes.The 'disallowed genes' of pancreatic beta-cells are a group of genes whose expression is specifically inhibited in beta-cells to avoid interference with critical beta-cell functions.Recent work has identified over 60 highly selectively repressed genes in pancreatic beta-cells,including the two 'founder members' of this group,lactate dehydrogenase A (Ldha) and monocarboxylate transporter-1 (Mct1/Slc16a1).Multiple mechanisms are involved in inactivation of 'disallowed genes',including histone modifications and microRNA-mediated silencing.Activating mutations in the Mct1 promoter may lead to exercise-induced hyperinsulinism hypoglycemia.Ldha expression in the beta-cells is upregulated in human type 2 diabetes and rodent models of type 2 diabetes.Thus,in the future,targeting of deregulated ' disallowed genes' may provide new therapeutic approaches for type 2 diabetes.