A novel classification of type 2 diabetes based on genome informatics

胰腺b细胞的葡萄糖刺激胰岛素分泌缺陷以及肌肉、肝脏和脂肪组织中的胰岛素抵抗是2型糖尿病患者肝纤维化的主要原因。本研究的目的是建立一个新的分类2型糖尿病作为一种多基因疾病的基础上，遗传易感性受损的胰岛素分泌或insulin resistance.We先前已表明，基因突变的肝细胞核因子（HNF）-4a和HNF-1a基因导致的2型糖尿病的特点是胰岛素分泌受损的形式。T1301突变是HNF-4a基因中相对罕见的遗传变异，其影响DNA结合结构域中的保守氨基酸。我们通过对777名日本受试者的病例对照研究，研究了多态性在2型糖尿病发展中的意义。2型糖尿病组T1301突变频率显著高于对照组（p=0.015，OR 4.3，95%CI 1.24-14.98）。为了阐明HNF-4a在葡萄糖刺激的胰腺b细胞胰岛素分泌中的作用，我们通过Cre-Lox P系统产生了b细胞特异性HNF-4a敲除小鼠。HNF-4a基因敲除小鼠在葡萄糖负荷后表现出葡萄糖耐受不良和胰岛素反应受损。膜片钳实验显示，KATP通道的电流密度在基因敲除小鼠中显著增加，表明KATP通道功能障碍。我们还研究了HNF-1a在胰腺B细胞中的靶基因，以阐明HNF-1a糖尿病的分子机制。我们发现，collectrin，最近克隆的肾脏特异性基因的未知功能，是一个新的目标HNF-1a在胰腺B细胞。Collectrin与SNARE复合物结合并促进SNARE复合物的形成。Collectrin是一种新的SNARE复合物形成调节剂，并控制胰岛素分泌。

Defective glucose-stimulated insulin secretion from pancreatic b-cells and insulin resistance in muscle, liver, and adipose tissue are the main cause of huperglycemia in type 2 diabetes. The purpose of the present study is to establish of a novel classification of type 2 diabetes as a polygenic disease, based on the genetic susceptibility to impaired insulin secretion or insulin resistance.We have previously shown that genetic mutations in the hepatocyte nuclear factor (HNF)-4a and HNF-1a genes cause a form of type 2 diabetes characterized by impaired insulin secretion. T1301 mutation is a relatively uncommon genetic variation in the HNF-4a gene, which affects a conserved amino acid in the DNA binding domain. We examined the significance of the polymorphism in the development of type 2 diabetes by case-control study with 777 Japanese subjects. The frequency of the T1301 mutation was significantly higher in the group of type 2 diabetes compared with control group (p=0.015, odds ratio 4.3, 95% Cl 1.24-14.98). To clarify the contribution of HNF-4a in glucose-stimulated insulin secretion from pancreatic b-cells, we generated b-cell specific HNF-4a knockout mice by Cre-Lox P system. HNF-4a knockout mice exhibited glucose intolerance and an impaired insulin response after glucose load. Patch clamp experiments revealed that the current density was significantly increased in the knockout mice, indicating the dysfunction of KATP channel in the knockout mice. We also studied the target genes of HNF-1a in pancreatic b-cells to clarify the molecular mechanism of HNF-1a diabetes. We found that collectrin, a recently cloned kidney specific gene of unknown function, is a novel target of HNF-1a in pancreatic b-cells. Collectrin bound to SNARE complex and facilitated SNARE complex formation. Collectrin is a novel regulator of SNARE complex formation and controls insulin secretion.