Abstract
Methylxanthines such as caffeine and theophylline are known to inhibit glucose transport. We have studied such inhibition in the glucose transporter type 1 deficiency syndrome (Glut1DS) by erythrocyte glucose transport assays. Data from four patients with individual mutations in the GLUT1 gene are discussed: patient 1 (hemizygosity), 3 (S66F), 15 (368Ins23), and 17 (R333W). Zero-trans influx of 14C-labeled 3-O-methyl glucose (3-OMG) into erythrocytes of patients is reduced (patient 1, 51%; 3, 45%; 15, 31%; 17, 52%) compared with maternal controls. Inhibition studies on patients 1, 3, 17, and maternal controls show an IC50 for caffeine of approximately 1.5 mM both in controls (n = 3) and patients (n = 3) at 5 mM 3-OMG concentration. In the same two groups, kinetic studies show that 3 mM caffeine significantly decreases Vmax (p < 0.005), whereas the decrease in Km is significant (p < 0.01) only in the three controls and one patient (patient 3). Kinetic data from individual patients permit us to speculate that the interactions between caffeine and Glut1 are influenced by the mutation. Three mM caffeine also inhibits the transport of dehydroascorbic acid (DHA), another substrate for Glut1. The combined effects of caffeine (3 mM) and phenobarbital (10 mM) on glucose transport, as determined in patient 15 and the maternal control, show no additive or synergistic inhibition. These data indicate that caffeine and phenobarbital have similar Glut1 inhibitory properties in these two subjects. Our study suggests that Glut1DS patients may have a reduced safety margin for methylxanthines. Consumption of methylxanthine-containing products may aggravate the neurologic symptoms associated with the Glut1DS.
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Abbreviations
- DHA:
-
dehydroascorbic acid
- GLUT1:
-
facilitated glucose transporter type 1 gene
- Glut1:
-
facilitated glucose transporter type 1 protein
- Glut1DS:
-
glucose transporter type 1 deficiency syndrome
- 3-OMG:
-
3-O-methyl-D-glucose
- >Vmax:
-
maximal transport velocity
- >Km:
-
substrate affinity
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Acknowledgements
The authors thank Pamela Kranz-Eble for skillful assistance in the laboratory and David Diuguid, M.D., Hematology Laboratory, Columbia Presbyterian Medical Center, for blood cell counts. CPD anticoagulant solution was generously provided by Baxter Healthcare Corporation, Fenwal Division, Deerfield, IL 60014, U.S.A.
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Ho, YY., Yang, H., Klepper, J. et al. Glucose Transporter Type 1 Deficiency Syndrome (Glut1DS): Methylxanthines Potentiate GLUT1 Haploinsufficiency In Vitro. Pediatr Res 50, 254–260 (2001). https://doi.org/10.1203/00006450-200108000-00015
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DOI: https://doi.org/10.1203/00006450-200108000-00015
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