A novel classification of type 2 diabetes based on genome informatics

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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.