Effect of Acute Insulin-Induced Hypoglycemia on Fetal versus Adult Brain Fuel Utilization, Assessed by 13C MRS Isotopomer Analysis of [U-13C]Glucose Metabolites

Abstract

Tight glycemic control during diabetic pregnancy has been shown to significantly reduce the occurrence of congenital malformations and other effects of maternal diabetes on the offspring. However, intensive insulin therapy often causes recurring acute maternal hypoglycemia, which has been found to be harmful to the developing fetus, although the mechanisms involved are not clear. The aim of our work was to study the effect of acute insulin-induced maternal hypoglycemia on glucose metabolism in the fetal brain. To this end, near-term pregnant New Zealand rabbits were rendered hypoglycemic, and [U-¹³C]glucose was infused into maternal circulation. The metabolic fate of the ¹³C-labeled glucose was then studied in fetal brain extracts by ¹³C NMR isotopomer analysis, together with conventional biochemical assays of glucose and lactate levels in both plasma and brain. For comparison [U-¹³C]glucose was also administered to insulin-induced hypoglycemic young adult rabbits. Our results showed that while plasma glucose levels were significantly reduced (∼70%) relative to controls, no changes in cerebral glucose levels could be detected. Lactate levels were found to be significantly decreased in hypoglycemic fetal plasma and brain. No differences in lactate levels between control and hypoglycemic young rabbit plasma and brain were observed. These differences were attributed to the utilization of lactate as an energy substrate in the fetal brain, but not in the adult brain. Higher relative ¹³C enrichments of most glucose metabolites, except lactate, in the hypoglycemic fetal and young rabbit brains, observed by ¹³C NMR, stem from reduced endogenous plasma glucose pools, thereby diluting the labeled glucose to a lower extent. The relative glucose (or glucose-derived lactate) flux via the pyruvate carboxylase and pyruvate dehydrogenase pathways (PC/PDH ratio) was not altered under hypoglycemic conditions in the fetal brain for both glutamine and glutamate, but significantly increased in the adult brain for both glutamine and glutamate. The presented data indicate the ability of the fetal brain to maintain energy metabolism during acute hypoglycemia, via lactate utilization. The increase in the adult PC/PDH ratio was suggested by us to stem from increased PC activity, in order to replenish TCA cycle intermediates.