Regulation of Pacreatic β-cell Function by Transcription Factors.

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Transcription factors play important roles in the development, differentiation, regeneration and maintenance of the differentiated phenotype of pancreatic β-cells. We have determined a complete structure of mouse and human PAX-4, a transcription factor essential for the development of pancreatic β-cells. We also investigated the role of hepatocyte nuclear factor (HNF) -1α in the β-cells. Mutations of the HNF-1α gene cause MODY3, a subtype of type 2 diabetes. We overexpressed a dominant negative mutant of HNF-1α in MIN6 cells and analyzed insulin secretion in response to various secretagogues. Suppression of HNF-1α in MIN6 cells severely impaired potentiation of insulin secretion by arginine, whereas glucose- and leucine-stimulated insulin secretion was intact. Our findings delineate the complex nature of β-cell failure in MODY3 patients.To investigate the mechanisms regulating "β-cell mass", we next studied the diseases causing changes in "β-cell mass". Wolfram syndrome is a rare autos … More omal recessive disorder characterized by diabetes mellitus, optic atrophy, diabetes insipidus and deafness. In the patients, pancreatic β-cells are reported to be selectively lost. We have identified a gene, named WFS1, by positional cloning. The gene encodes a novel transmembrane protein of 890 amino acids, which is not homologous to any proteins in the database. Preliminary data suggest that WFS1 protein is in endoplasmic reticulum and expressed in limited subsets of neurons in mouse brain. Function of WFS1 protein and mechanisms by which β-cells are selectively lost in the patients need to be clarified. Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a condition characterized by persistent insulin secretion in the presence of hypoglycemia. In some patients with PHHI, β-cell hyperplasia, called nesidioblastosis, is often observed and mutations were identified in the genes encoding ATP-sensitive potassium channel (KィイD2ATPィエD2). We identified three mutations in the SUR1 (one of two subunits of KィイD2ATPィエD2) gene in Japanese patients with PHHI. By in vitro functional studies, it was revealed that one of the mutations (R1420C) impaired cooperative binding of adenine nucleotides to SUR1. Less