OP-8：The role of plasma membrane type sialidase gene NEU3 and GM3 synthase gene GM3S (SIAT9) on the pathogenesis of type 2 diabetes mellitus in Japanese.

Susumu Suzuki¹，Yoshinori Hinokio¹，Hiroshi Hirai¹，Taeko Miyagi²，Yoshitomo Oka¹.

¹Tohoku University Graduate School of Medicine，Department of Molecular Metabolism and Diabetes，²Miyagi Prefectural Cancer Center, Department of Biochemistry.

It has been previously reported that gangliosides and sialic acids play an important role in both type1 and type 2 diabetes. We generated mice overexpressing plasma membrane-associated sialidase (Neu3) specific for gangliosides (J Biol Chem, 2003). The mice developed severe insulin-resistant phenotype of diabetes. In addition, the mice lacking GM3 synthase (SIAT 9) were reported to be protected from high fat diet-induced insulin resistance. This study was designed to investigate the possible contribution of single nucleotide polymorphisms (SNPs) in NEU3 and SIAT9 to type 2 diabetes development.

We screened SNPs in 345 Japanese diabetic patients and 387 controls. We identified two SNP in the promoter region (C/T) and exon 3 (A/G) in Neu3 gene. The allele frequencies of the SNP (C/T) were different between diabetic and control group (p<0.001). The values of body mass index, plasma insulin at fasting state and HOMA(R) of subjects with normal glucose tolerance were higher in T/T genotype than in C/C genotype in the SNP.

The frequencies of haplotype-C of T-allele in -32 promoter region and G-allele in exon3 in SIAT9 were different between diabetic and control group (p<0.01). The subjects with haplotype-C had lower sum of insulin levels during 75g oral glucose tolerance test (p<0.001), insulinogenic index (p<0.005) and lower HOMA(R) (p<0.05) than those with other haplotypes.

From these results, it may be concluded that Neu3 and SIAT 9 genes may play an important role in the pathogenesis of diabetes mellitus. This is the first report showing the Neu3 and SIAT 9 gene polymorphism to be associated with the development of type 2 diabetes in Japanese subjects.