MOUSE EMBRYONIC CARDIAC METABOLISM UNDER EUGLYCEMIC AND HYPOGLYCEMIC CONDITIONS

Children of mothers with insulin-dependent diabetic mothers (IDDM) hav e a 2-4 times higher incidence of congenital birth defects as compared to the general population, including cardiac abnormalities, of unknow n etiology. Using rodent embryos to explore potential teratogenic fact ors of the altered IDDM metabolism, it has been shown that exposure to hypoglycemia in vitro results in a variety of defects, including card iac malformations. Since pregnant diabetics experience frequent episod es of low blood glucose, it was hypothesized that hypoglycemia may pla y a role in the generation of heart abnormalities seen in children bor n to IDDM mothers. Several studies have indicated that during embryoge nesis the heart is dependent on glucose for energy production such tha t, under hypoglycemic conditions, insufficient amounts of ATP may be p roduced resulting in abnormalities. To test this hypothesis, cardiac A TP content was monitored in D10-D12 (plug day = D1) hearts. In additio n, the contribution of glycolysis and the Krebs cycle to ATP productio n was monitored. D10 hearts exposed to euglycemic control conditions w ere found to be primarily dependent on glycolysis for ATP production f rom glucose before switching to the Krebs cycle and oxidative phosphor ylation for energy production from this substrate on D11. Exposure to hypoglycemia did not alter the timing of this maturation process or de plete cardiac ATP content. However, cardiac lactate levels increased a pproximately twofold in the presence of hypoglycemia on D10. Since inc reased concentrations of lactate are harmful to many tissues and have been shown to be detrimental to the adult rat heart, lactic acidosis m ay explain the origin of cardiac defects produced by hypoglycemia, and not a deficiency of ATP. (C) 1996 Wiley-Liss, Inc.