Regulation of Pacreatic β-cell Function by Transcription Factors.

转录因子对胰腺 β 细胞功能的调节。

• 批准号: 10671074
• 负责人: TANIZAWA Yukio
• 金额: $ 2.05万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671074/
• 关键词: diabetes mellitus; Wolfram syndrome; optic atrophy; PAX-4; endoplasmic reticulum; HNF-1α; insulin; persistent hyperinsulinemic hypoglycemia of infancy; Wolframの症候群; 難聴; 遺伝子; インスリン分泌; 転写因子; MODY

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

转录因子在胰岛β细胞的发育、分化、再生和分化表型的维持中起重要作用。我们已经确定了小鼠和人PAX-4的完整结构，PAX-4是胰腺β细胞发育所必需的转录因子。我们还研究了肝细胞核因子（HNF）-1α在β细胞中的作用。HNF-1α基因突变导致MODY 3，这是2型糖尿病的一种亚型。我们在MIN 6细胞中过表达HNF-1α的显性失活突变体，并分析了胰岛素对各种促分泌素的分泌反应。在MIN 6细胞中抑制HNF-1α严重损害精氨酸对胰岛素分泌的增强作用，而葡萄糖和亮氨酸刺激的胰岛素分泌是完整的。我们的研究结果描述了MODY 3患者β细胞衰竭的复杂本质。为了研究调节“β细胞群”的机制，我们接下来研究了引起“β细胞群”变化的疾病。沃尔夫勒姆综合征是一种罕见的汽车 ...更多信息 以糖尿病、视神经萎缩、尿崩症和耳聋为特征的omal隐性疾病。在患者中，据报道胰腺β细胞选择性丢失。我们已经确定了一个基因，命名为WFS 1，通过定位克隆。该基因编码一种新的跨膜蛋白，由890个氨基酸组成，与数据库中的任何蛋白质都不同源。初步数据表明，WFS 1蛋白是在内质网和表达在有限的子集的神经元在小鼠大脑。WFS 1蛋白的功能和β细胞在患者中选择性丢失的机制需要澄清。婴儿持续性高胰岛素血症性低血糖症（PHHI）是一种以低血糖症存在时持续胰岛素分泌为特征的疾病。在一些PHHI患者中，经常观察到β细胞增生，称为胰岛母细胞增多症，并在编码ATP敏感性钾通道（K通道D2 ATP通道D2）的基因中发现突变。我们在日本PHHI患者中发现了SUR 1（KATP D2亚基之一）基因的三个突变。通过体外功能研究，发现其中一个突变（R1420 C）损害腺嘌呤核苷酸与SUR 1的协同结合。少

项目成果

Tanizawa Y et al.: "Genetic Analysis of Japanese Patients with Persistent HyperinsulinemicHypoglycemia of Infancy"Diabetes. 49. 114-120 (2000)

Tanizawa Y等人：“患有婴儿期持续性高胰岛素低血糖症的日本患者的基因分析”。

Inoue H. et al.: "isolation of full length cDNA of mouse PAX4 gene and identification of its human homologue."Biochem Biophys Res Com. 243. 628-633 (1998)

Inoue H.等人：“小鼠PAX4基因全长cDNA的分离及其人类同源物的鉴定。”Biochem Biophys Res Com。

Tanizawa Y et al.: "Overexpression of Dominant Negative Mutant Hepatocyte Nuclear Factor (HNF)-1α Induced Insilin Secretion in MIN6 Cells."Diabetologia. 42. 887-891 (1999)

Tanizawa Y 等人：“显性阴性突变肝细胞核因子 (HNF)-1α 诱导 MIN6 细胞中胰岛素分泌。”42. 887-891 (1999)

Norman RA et al.: "Abesent of genetic variation in some obesity candidate genes(GLP1R、ASIP、MC4R、MC5R)among pima indans"Int J Oves Relat Metab Disord. 23. 163-165 (1999)

Norman RA 等人：“pima indans 中某些肥胖候选基因（GLP1R、ASIP、MC4R、MC5R）不存在遗传变异”Int J Oves Relat Metab Disord 23. 163-165 (1999)

Yukio Tanizawa: "Overexpression of Dominant Negative Hepatocyte Nuclear Factor(HNF)-1α Inhibits Arginine-Induced Insulin Secretion in MIN6 Cells." Diabetologia. 42(in press). (1999)

Yukio Tanizawa：“显性阴性肝细胞核因子 (HNF)-1α 的过度表达抑制 MIN6 细胞中精氨酸诱导的胰岛素分泌。”(1999 年出版)。