Effect of endogenous beta-hydroxybutyrate on brain glucose metabolism in fetuses of diabetic rabbits, studied by (13)C magnetic resonance spectroscopy.
The aim of our research was to uncover perturbations in in-utero fetal cerebral metabolism resulting from hyperglycemia and hyperketonemia, which occur during maternal diabetes. Therefore, we examined the effects of glucose overload and hyperketonemia on glucose metabolism in the diabetic fetal brain; more specifically, the effect of diabetes on the glucose flux via pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) and subsequent metabolism in the fetal cerebral tricarboxylic acid (TCA) cycle were examined, as well as the effect of diabetes on energy fuel utilization in the neurons and glia. Diabetes was induced in pregnant rabbits, and towards term, [U-(13)C(6)]glucose was infused into maternal circulation, and [(13)C]glucose metabolites were subsequently studied in fetal brain extracts by (13)C MRS isotopomer analysis. Significantly elevated maternal and fetal plasma glucose levels (three- and up to fivefold, respectively) and fetal brain glucose levels (up to eightfold) accompanied by an increase of beta-hydroxybutyrate (beta-HBA) levels (approximately 20-fold) were found in the hyperketonemic diabetic animals, whereas fetal cerebral lactate levels were decreased. Alterations in the (13)C labeling patterns, mainly of glutamine, led us to suggest that the entry of beta-HBA-derived acetyl-CoA inhibits formation and entry of labeled glucose-derived acetyl-CoA into the TCA cycle, mainly in glia. Accumulation of glucose and the decrease in lactate levels in the fetal brain are most likely the result of an inhibitory effect of beta-HBA on glycolysis. In addition, loss of (13)C enrichment of TCA cycle intermediates and products, glutamate and glutamine, in the hyperketonemic diabetic fetal brain may be attributed to the effect of beta-HBA fuel utilization by the fetal brain.
Lapidot
Aviva
A
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. aviva.lapidot@weizmann.ac.il
Haber
Shelley
S
D020155:3-Hydroxybutyric Acid / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001921:Brain / Q000196:embryology*; D002247:Carbon Isotopes; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000378:metabolism*; D011270:Pregnancy, Animal / Q000378:metabolism*; D011766:Pyruvate Carboxylase / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D011817:Rabbits
D000596:Amino Acids; D001786:Blood Glucose; D002247:Carbon Isotopes; D011768:Pyruvate Dehydrogenase Complex; D019344:Lactic Acid; D011766:Pyruvate Carboxylase; D005947:Glucose; D020155:3-Hydroxybutyric Acid