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Annals of Clinical & Laboratory Science 32:114-122 (2002)
© 2002 Association of Clinical Scientists

Analysis of Polymorphism of the GLUT2 Promoter in NIDDM Patients and its Functional Consequence to the Promoter Activity

Ji-young Cha1, Hyon-suk Kim2, Ha-il Kim1, Seung-soon Im1, So-youn Kim1, Jae-woo Kim1, Byung-il Yeh1 and Yong-ho Ahn1
1 Department of Biochemistry & Molecular Biology and Institute of Genetic Science, and
2 Department of Clinical Pathology, Yonsei University College of Medicine, Seoul, Korea

Address correspondence to Yong-ho Ahn, M.D., Ph.D., Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul 120-752, Korea; tel 82 2 361 5182; fax 82 2 312 5041; e-mail yha111{at}yumc.yonsei.ac.kr.

Glucose transporter type 2 (GLUT2), along with glucokinase, has been implicated to participate in glucose-induced insulin secretion in pancreatic ß-cells. Recently, several sequence variations in the promoter of GLUT2 have been identified in patients with non-insulin dependent diabetes mellitus (NIDDM), but the functional effects of these polymorphisms on promoter activity have not previously been studied. We compared the incidence of sequence variations in the GLUT2 promoter in 100 normal subjects and 100 NIDDM patients. Sequencing of the promoter region (-294 to +301) revealed that an A->G variant at position -44 was found in 45 of 100 NIDDM patients, but only in 23 of 100 normal subjects. In addition, -269 A->C and +103 A->G mutations were identified in a single diabetic patient. Electrophoretic mobility shift assays using double-stranded oligonucleotide containing -44A as a probe showed a clearly shifted band of DNA-protein. To examine whether the sequence variation at position -44 affects the promoter activity, we carried out in vitro transfection experiments. Site-specific mutagenesis at position -44 region from A to C, T, or G resulted in reductions of CAT activity by 52.3%, 63.8%, and 63.6%, respectively. The -269 A->C and +103 A->G mutations also decreased the promoter activity. These results suggest that polymorphisms at positions -269, -44, or +103 may affect GLUT2 gene transcription, possibly associated with reduced expression of the GLUT2 gene in NIDDM patients.

Keywords: glucose transporter type 2, gene polymorphisms, noninsulin dependent diabetes mellitus




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