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

由于大多数日本NIDDM患者的特点是葡萄糖诱导的胰岛素分泌受损，参与调节葡萄糖诱导的胰岛素分泌的编码蛋白的基因(S)是很好的候选NIDDM易感基因。我们重点研究了胰岛β细胞表达的离子通道(ATP敏感的K~+通道和电压依赖性的Ca~(++)通道)和胃肠肽受体。我们对这些分子的结构和功能进行了研究，并确定了它们的基因结构。主要结果如下：1.ATP敏感的K~+(K_&lt；ATP&gt；)通道。β细胞通道含有磺脲受体(SUR1)和内向整流子Kir6.2(BIR)，SUR1广泛用于治疗NIDDM。有一类磺脲类受体决定了三磷酸腺苷和格列本脲的敏感性。SUR1和Kir6.2基因位于人类染色体11p.15.1处。在所研究的日本人中，有两种类型的Kir6.2等位基因。SUR1基因的一些突变被证明与婴儿时期的高胰岛素血症有关。这些基因在NIDDM发病中的作用目前尚不清楚。2.电压依赖性钙通道(VDCC)。VDCC在胰岛β细胞中的功能表达需要α-亚基(CACN4)和β-亚基。CACN4基因全长150 kb，有39个外显子。人CACN4基因(CACNL1A2)存在多个多态性。CACNLB3β亚基基因全长8kb，13个外显子。3.GIP受体。人GIP受体基因的克隆表明，人GIP受体是一个由466个氨基酸组成的蛋白质。人类GIP基因全长-13.8kb，有14个外显子，其编码胰岛素分泌相关蛋白的基因的克隆将为了解日本NIDDM患者发病的遗传因素提供基础。

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.