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

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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.