GLUT1-deficiency: Barbiturates potentiate haploinsufficiency in vitro

Barbiturates are known to inhibit glucose transport mediated by the facilit ative sugar transporter GLUT1. We have studied such inhibition in children with GLUT1-deficiency. Zero-trans influx of C-14-labeled 3-O-methyl glucose (30MG) into erythrocytes of patients (n = 3) was 35% of controls (n = 6). Preincubation with 10 mM phenobarbital or pentobarbital reduced patients' 3 0MG influx to 17%. In patients and controls, preincubation with barbiturate s significantly decreased V-max in a dose-dependent manner (for pentobarbit al, IC50 = 0.84 mM, patient 2). The apparent K-m in individuals remained la rgely unchanged. Three-OMG influx without preincubation resulted in a stron ger inhibition at lower barbiturate concentrations. The patients' data are discussed in the light of individual missense mutations (patient I: R126L a nd K256V; patient 2: T310I; patient 3: S66F) in the GLUT1 gene. In conclusi on, in controls and patients with GLUT1-deficiency barbiturates interact wi th GLUT1, lowering its intrinsic activity. The use of barbiturates in this condition for anesthesia or as anticonvulsants could therefore potentially aggravate the existing glucose transport defect and may put these patients at increased risk.