To assess the contribution of GLUT1 and GLUT4 genes to NIDDM susceptibility in Japanese population, we performed population studies using RFLP markers. We found the strong association between XbaI polymorphism at GLUT1 gene and NIDDM, but no association between KpnI polymorphism at GLUT4 gene and NIDDM. Based on these results, molecular scanning of GLUT1 gene was performed using SSCP and direct sequencing in Japanese population, to substantiate the gene defect predisposing to NDDM. Although silent mutations were found, the meaningful mutations within the coding regions were not demonstrated. Thus the positive association observed in population study may be spurious or due to the abnormalities in non-coding regions such as promoter or other regulatory elements at GLUT1 gene.