Gatifloxacin affects GLUT1 gene expression and disturbs glucose homeostasis in vitro.

Gatifloxacin may induce life-threatening dysglycemia. The facilitated glucose transporter type 1 (GLUT1) protein is ubiquitously expressed in many tissues. Disturbed GLUT1 protein function weakens the systemic glycemic control and may cause dysglycemia. In this study we demonstrate that gatifloxacin modulates the transcription and reduces the expression and function of GLUT1 gene in HepG2 cells. When treated with gatifloxacin at concentrations of 3.4 mug/ml (8.4 muM) and 17 mug/ml (42 muM), GLUT1 promoter activity was stimulated by 2.8 and 3.8 folds, GLUT1 mRNA expression was decreased by 41% and 31%, and glucose uptake was decreased by 41% and 52%, respectively. Our findings imply that disturbed GLUT1 gene expression and protein function may underlie the dysglycemic effect of gatifloxacin.

APOE genotype-function relationship: evidence of -491 A/T promoter polymorphism modifying transcription control but not type 2 diabetes risk.

BACKGROUND: The apolipoprotein E gene (APOE) coding polymorphism modifies the risks of Alzheimer's disease, type 2 diabetes, and coronary heart disease. Aside from the coding variants, single nucleotide polymorphism (SNP) of the APOE promoter has also been shown to modify the risk of Alzheimer's disease. METHODOLOGY/PRINCIPAL FINDINGS: In this study we investigate the genotype-function relationship of APOE promoter polymorphism at molecular level and at physiological level: i.e., in transcription control of the gene and in the risk of type 2 diabetes. In molecular studies, the effect of the APOE -491A/T (rs449647) polymorphism on gene transcription was accessed by dual-luciferase reporter gene assays. The -491 A to T substitution decreased the activity (p<0.05) of the cloned APOE promoter (-1017 to +406). Using the -501 to -481 nucleotide sequence of the APOE promoter as a 'bait' to screen the human brain cDNA library by yeast one-hybrid system yielded ATF4, an endoplasmic reticulum stress response gene, as one of the interacting factors. Electrophoretic-mobility-shift assays (EMSA) and chromatin immuno-precipitation (ChIP) analyses further substantiated the physical interaction between ATF4 and the APOE promoter. Over-expression of ATF4 stimulated APOE expression whereas siRNA against ATF4 suppressed the expression of the gene. However, interaction between APOE promoter and ATF4 was not -491A/T-specific. At physiological level, the genotype-function relationship of APOE promoter polymorphism was studied in type 2 diabetes. In 630 cases and 595 controls, three APOE promoter SNPs -491A/T, -219G/T (rs405509), and +113G/C (rs440446) were genotyped and tested for association with type 2 diabetes in Hong Kong Chinese. No SNP or haplotype association with type 2 diabetes was detected. CONCLUSIONS/SIGNIFICANCE: At molecular level, polymorphism -491A/T and ATF4 elicit independent control of APOE gene expression. At physiological level, no genotype-risk association was detected between the studied APOE promoter SNPs and type 2 diabetes in Hong Kong Chinese.