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

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障碍，因此编码参与调节葡萄糖诱导的胰岛素分泌的蛋白质的基因是NIDDM易感基因的良好候选基因。我们关注的是离子通道（atp敏感的K^+通道和电压依赖性的Ca^+通道）和胃肠道多肽（GIP）受体在胰腺β细胞中的表达。我们已经研究了这些分子的结构和功能，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>通道包括磺酰脲受体（SUR1），广泛用于治疗NIDDM和内向整流Kir6.2 （BIR）。有一个磺脲受体家族决定atp和格列苯脲的敏感性。在人类染色体上，SUR1和Kir6.2基因聚集在11p.15.1位点。日本人的Kir6.2等位基因有两种类型。SUR1基因的一些突变被证明是婴儿期高胰岛素性低血糖症的原因。这些基因在NIDDM发展中的作用目前尚不清楚。电压依赖性钙通道（VDCC）。胰腺β细胞中VDCC的功能表达需要α -亚基（CACN4）和β -亚基。CACN4的基因长度超过150 kb，有39个外显子。人类CACN4基因（CACNL1A2）存在许多多态性。β -亚基CACNLB3的基因长度为-8kb，有13个外显子。GIP受体。人类GIP受体cDNA的克隆表明，人类GIP受体是一个由466个氨基酸组成的蛋白。人类GIP基因全长13.8kb，有14个外显子。克隆参与胰岛素分泌的蛋白编码基因，为了解日本NIDDM患者发展的遗传因素提供了基础。

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.