A novel classification of type 2 diabetes based on genome informatics

胰腺b细胞葡萄糖刺激的胰岛素分泌缺陷和肌肉、肝脏和脂肪组织的胰岛素抵抗是2型糖尿病高血糖的主要原因。本研究的目的是基于对胰岛素分泌受损或胰岛素抵抗的遗传易感性，建立2型糖尿病作为多基因疾病的新分类。我们之前已经证明，肝细胞核因子(HNF)-4a和HNF-1a基因的基因突变导致以胰岛素分泌受损为特征的2型糖尿病。T1301突变是HNF-4a基因中相对少见的遗传变异，影响DNA结合域的一个保守氨基酸。我们通过对777名日本受试者的病例对照研究，检验了多态性在2型糖尿病发生中的意义。2型糖尿病组T1301突变频率明显高于对照组（p=0.015，比值比4.3,95% Cl 1.24-14.98）。为了阐明HNF-4a在葡萄糖刺激胰腺b细胞胰岛素分泌中的作用，我们通过Cre-Lox P系统培养了b细胞特异性HNF-4a敲除小鼠。HNF-4a基因敲除小鼠表现出葡萄糖耐受不良和葡萄糖负荷后胰岛素反应受损。膜片钳实验显示，敲除小鼠的电流密度明显增加，提示敲除小鼠的KATP通道功能障碍。我们还研究了胰腺b细胞中HNF-1a的靶基因，以阐明HNF-1a糖尿病的分子机制。我们发现，最近克隆的肾特异性基因collectrin功能未知，是胰腺b细胞中HNF-1a的新靶点。集合蛋白与SNARE复合体结合，促进SNARE复合体的形成。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.