Lapidot Aviva, Haber Shelley
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
Brain Res Dev Brain Res. 2002 Apr 30;135(1-2):87-99. doi: 10.1016/s0165-3806(02)00347-4.
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.
我们研究的目的是揭示母体糖尿病期间发生的高血糖和高酮血症导致的子宫内胎儿脑代谢紊乱。因此，我们研究了葡萄糖过载和高酮血症对糖尿病胎儿脑葡萄糖代谢的影响；更具体地说，研究了糖尿病对通过丙酮酸脱氢酶（PDH）和丙酮酸羧化酶（PC）的葡萄糖通量以及胎儿脑三羧酸（TCA）循环中后续代谢的影响，以及糖尿病对神经元和神经胶质细胞中能量燃料利用的影响。对怀孕兔子诱导糖尿病，在接近足月时，将[U-(13)C(6)]葡萄糖注入母体循环，随后通过(13)C MRS同位素异构体分析在胎儿脑提取物中研究[(13)C]葡萄糖代谢物。在高酮血症糖尿病动物中发现母体和胎儿血浆葡萄糖水平显著升高（分别为三倍和高达五倍）以及胎儿脑葡萄糖水平（高达八倍），同时β-羟基丁酸（β-HBA）水平升高（约20倍），而胎儿脑乳酸水平降低。(13)C标记模式的改变，主要是谷氨酰胺的改变，使我们认为β-HBA衍生的乙酰辅酶A的进入抑制了标记的葡萄糖衍生的乙酰辅酶A进入TCA循环，主要是在神经胶质细胞中。胎儿脑中葡萄糖的积累和乳酸水平的降低很可能是β-HBA对糖酵解的抑制作用的结果。此外，高酮血症糖尿病胎儿脑中TCA循环中间体和产物、谷氨酸和谷氨酰胺的(13)C富集的丧失可能归因于胎儿脑对β-HBA燃料的利用。
