Studies on the genes susceptible to non-insulin dependent diabetes mellitus in Japanese.

日本人非胰岛素依赖型糖尿病易感基因的研究。

基本信息

批准号：
06404036
负责人：
SEINO Susumu
金额：
$ 19.9万
依托单位：
Chiba University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1996
项目状态：
已结题

项目摘要

Since most of Japanese NIDDM patients are characterized by impairement in glucose-induced insulin secretion, the gene (s) encoding proteins that are involved in the regulation of glucose-induced insulin secretion are good candidates for NIDDM susceptibility genes. We have focused on the ion channels (ATP-sensitive K^+ channels and voltagedependent Ca^+ channels) and gastrointenstinal polypeptide (GIP) receptor expressed in pancreatic beta cells. We have studied the structures and functions on these molecules and also have determined their gene structures.The results are summarized as follows.1.ATP-sensitive K^+ (K_<ATP>) channels. The beta-cell K_<ATP> channel comprises a receptor for sulfonylurea (SUR1), widely used in the treatment of NIDDM and the inward rectifier Kir6.2 (BIR). There is a family of sulfonylurea receptors which determines the ATP-and glibenclamide-sensitivities. The genes for SUR1 and Kir6.2 are clusterd at 11p.15.1 on human chromosome. There are two types of Kir6.2 allele in Japanese subjects studied. Some mutations of the SUR1 gene are shown to be responsible for hyperinsulinemic liypoglycemia in infancy. The role of these genes in the development of NIDDM is unknown at present.2.Voltage-dependent calcium channels (VDCC). The functional expression of VDCC in pancreatic beta-cells requires both the alpha-subunit (CACN4) and a beta-subunit. The gene for CACN4 spans more than 150 kb and 39 exons. There are a number of polymorphisms in the human CACN4 gene (CACNL1A2). The gene for the beta-subunit CACNLB3 spans-8kb and 13 exons.3.GIP receptor. Cloning of cDNA encoding the human GIP receptor reveals that human GIP receptor is a 466 amino acid protein. The human GIP gene spans-13.8kb and has 14 exons.Cloning of the genes encoding the proteins involved in insulin secretion should provide a basis of understanding genetic factors contributing to the development of Japanese NIDDM patients.

由于大多数日本NIDDM患者的特征是葡萄糖诱导的胰岛素分泌受损，因此编码与葡萄糖诱导的胰岛素分泌有关的蛋白质的基因是NIDDM易感性基因的良好候选者。我们专注于在胰腺β细胞中表达的离子通道（对ATP敏感的K^+通道和伏特加依赖性CA^+通道）和胃固醇多肽（GIP）受体。我们已经研究了这些分子上的结构和功能，并确定了它们的基因结构。结果总结如下。1.ATP敏感的K^+（K_ <ATP>）通道。 β细胞K_ <ATP>通道包括一个用于磺酰尿素的受体（SUR1），该受体广泛用于NIDDM和内向整流器Kir6.2（BIR）的处理。有一个磺酰脲受体家族决定了ATP和Glibenclamide敏感性。 SUR1和KIR6.2的基因在人类染色体上的11p.15.1聚类。在研究的日本受试者中，Kir6.2等位基因有两种类型。 SUR1基因的某些突变被证明是在婴儿期导致高胰岛素liypoglycemia的原因。这些基因在NIDDM发展中的作用目前尚不清楚。2。电压依赖性钙通道（VDCC）。 VDCC在胰腺β细胞中的功能表达同时需要α-亚基（CACN4）和β-亚基。 CaCN4的基因跨越150 kb和39个外显子。人CaCn4基因中有许多多态性（CACNL1A2）。 Beta-subunit CACNLB3 SPANS-8KB和13个外显子的基因3.GIP受体。编码人GIP受体的cDNA的克隆表明，人GIP受体是466氨基酸蛋白。人类GIP基因跨13.8KB并具有14个外显子。编码胰岛素分泌所涉及的蛋白质的基因应提供理解有助于日本NIDDM患者发展的遗传因素的基础。