Miki T, Iwanaga T, Nagashima K, Ihara Y, Seino S
Department of Molecular Medicine, Chiba University Graduate School of Medicine, Japan.
Diabetes. 2001 Feb;50 Suppl 1:S48-51. doi: 10.2337/diabetes.50.2007.s48.
To determine the roles of the ATP-sensitive K+ (K(ATP)) channels in endocrine pancreas more directly, two types of genetically engineered Kir6.2 mice were developed: mice expressing a dominant-negative form of Kir6.2 specifically in beta-cells (Kir6.2G132S Tg mice) and mice lacking Kir6.2 (Kir6.2-/- or Kir6.2 null mice). The Kir6.2G132S Tg mice show severe impairment of K(ATP) channel function only in the beta-cells, whereas Kir6.2 null mice are completely defective in K(ATP) channel function in all of the cells in which Kir6.2 is a constituent of the K(ATP) channels, because of the disruption of Kir6.2. Both types of mice show abnormal architecture of the pancreatic islets. The number of beta-cells in Kir6.2G132S Tg mice decreases markedly with age, whereas that in Kir6.2-/- mice decreases slightly. alpha-Cells, which are normally present only in the periphery of pancreatic islets, also appear in the center of the islets in both Kir6.2G132S Tg and Kir6.2-/- mice. Interestingly, the number of peptide YY (PYY) and glucagon-positive cells is markedly increased in Kir6.2 null mice, whereas the number of PP cells and delta-cells is not altered. Apoptotic cells are detected by the TdT-mediated dUTP nick-end labeling (TUNEL) method at a high frequency in both Kir6.2G372S Tg and Kir6.2-/- mice compared with the respective controls. Thus, studies of Kir6.2G372S Tg and Kir6.2-/- mice indicate that K(ATP) channels play an important role in cell survival and differentiation in the endocrine pancreas.
为了更直接地确定ATP敏感性钾离子（K(ATP)）通道在内分泌胰腺中的作用，我们培育了两种基因工程化的Kir6.2小鼠：一种是在β细胞中特异性表达显性负性形式Kir6.2的小鼠（Kir6.2G132S转基因小鼠），另一种是缺乏Kir6.2的小鼠（Kir6.2-/-或Kir6.2基因敲除小鼠）。Kir6.2G132S转基因小鼠仅在β细胞中显示出K(ATP)通道功能的严重受损，而Kir6.2基因敲除小鼠由于Kir6.2的缺失，在所有以Kir6.2作为K(ATP)通道组成部分的细胞中，K(ATP)通道功能完全缺陷。这两种类型的小鼠均表现出胰岛结构异常。Kir6.2G132S转基因小鼠中的β细胞数量随年龄增长显著减少，而Kir6.2-/-小鼠中的β细胞数量略有减少。通常仅存在于胰岛周边的α细胞，在Kir6.2G132S转基因小鼠和Kir6.2-/-小鼠的胰岛中央也有出现。有趣的是，Kir6.2基因敲除小鼠中肽YY（PYY）和胰高血糖素阳性细胞的数量显著增加，而PP细胞和δ细胞的数量未改变。与各自的对照组相比，通过TdT介导的dUTP缺口末端标记（TUNEL）方法在Kir6.2G372S转基因小鼠和Kir6.2-/-小鼠中均高频检测到凋亡细胞。因此，对Kir6.2G372S转基因小鼠和Kir6.2-/-小鼠的研究表明，K(ATP)通道在内分泌胰腺的细胞存活和分化中起重要作用。
