Roles of ATP-sensitive K+ channels in cell survival and differentiation in the endocrine pancreas

Abstract

To determine the roles of the ATP-sensitive K+ (KATP) 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 β-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 KATP channel function only in the β-cells, whereas Kir6.2 null mice are completely defective in KATP channel function in all of the cells in which Kir6.2 is a constituent of the KATP channels, because of the disruption of Kir6.2. Both types of mice show abnormal architecture of the pancreatic islets. The number of β-cells in Kir6.2G132S Tg mice decreases markedly with age, whereas that in Kir6.2-/- mice decreases slightly. α-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 δ-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 kATP channels play an important role in cell survival and differentiation in the endocrine pancreas.