EFFECT OF MATERNAL DIABETES ON THE EXPRESSION OF GENES REGULATING FETAL BRAIN GLUCOSE-UPTAKE

Diabetes alters adult brain glucose uptake and glucose transporter 1 g ene expression. To investigate the effect of diabetes on genes regulat ing fetal brain glucose uptake, we examined the effect of moderate (bl ood glucose 10-16.7 mM, normoinsulinemia) and severe (blood glucose >1 6.8 mM, hypoinsulinemia) maternal diabetes on the expression of genes regulating fetal brain glucose uptake in the genetically nonobese diab etic mouse. In the moderately diabetic state, a 50% decline in fetal b rain GLUT1 mRNA levels was associated with a 20% increase in the corre sponding GLUT1 protein levels. Simultaneously, although fetal brain GL UT3 mRNA and protein levels were barely detectable, no change in hexok inase I enzyme mRNA, protein (115,000 and 1 00,000 M(r)) or activity, was noted. In the severe form of maternal diabetes GLUT1 protein was u nchanged, GLUT3 protein levels remained low, and a 2- to 3-fold increa se in the lower molecular form of the hexokinase I protein (100,000 M( r)) and enzyme activity occurred. These observations suggest that mode rate and severe forms of maternal diabetes do not affect the fetal bra in glucose transporter levels to a physiologically significant extent. The severe form of maternal diabetes, however, enhances 1.5- to 3-fol d the expression and activity of hexokinase I. This enzyme mediates th e rate-limiting step in brain glucose metabolism, namely the intracell ular conversion of glucose to glucose-6-phosphate.