The liver/pancreatic beta cell type glucose transporter (GLUT2) is expressed in the pancreatic beta cell, a glucose carrier with a low affinity for glucose but a high capacity for glucose transport. The expression of GLUT2 in the normal pancreatic islet is increased after exposure to high glucose, while it is decreased in model animal with non-insulin-dependent diabetes mellitus (NIDDM). In Pima Indians, to assess the genetic components of the acute insulin response (AIR) and NIDDM, polymorphic dinucleotide repeat regions in the GLUT2 gene were evaluated. Robust sib-pair linkage analyses suggest linkage between GLUT2 and AIR, but no linkage was observed with NIDDM. The coding region of the GLUT2 gene was screened for mutations using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. A single base change was identified in exon 3 in -5% of the study population. Although this base change resulted in an amino acid substitution (Thr110-Ile110), no significant association was noted between AIR and the mutation. We also screened for mutations using PCR-SSCP analysis in Japanese subjects. A single base silent polymorphism (Phe497, TTT-TTC) was identified in exon 10. Significant association was noted between TTC type and NIDDM (N = 78), compared to normal controls (N = 80). These data suggest the possibility that GLUT2 is one of the candidate genes for NIDDM.