Correlations between Maternal Metabolism and Deranged Development in the Offspring of Normal and Diabetic Rats

Abstract

In an attempt to define the pathogenesis of congenital malformations in diabetic pregnancy, a number of serum factors were determined in normal and diabetic pregnant rats and correlated to the outcome of gestation with the aid of multivariate linear regression analysis. The animals were from two different lines of Sprague-Dawley rats with documented differences in rates of fetal dysmorphogenesis in diabetic pregnancy. The diabetic rats increased less in body weight than the normal rats, yet displayed increased liver and kidney weights. The serum concentrations of glucose, P-hydroxybutyrate, triglycerides, the branched-chain amino acids, and asparagine, proline, alanine, citrulline, tyrosine, and ornithine were increased by diabetes. In contrast, IGF-I, glutamic acid, glutamine, cystine, and lysine were decreased in the serum of the diabetic pregnant rats. The maternal metabolic imbalance exerted profound effects on embryonic development. Thus, the embryos of the diabetic rats were smaller, had fewer somites, and contained less DNA and protein than the control embryos. In addition, the resorption and malformation rates were increased in the embryos of the diabetic rats. The regression analysis of the data revealed significant interrelationships between adverse embryonic outcome (rates of malformations and resorptions) and the maternal serum concentrations of glucose, triglycerides, P-hydroxybutyrate, branched-I---Diabetic pregnancy is associated with an increased risk of fetal maldevelopment (1-3). The pathogenesis of congenital malformations in the offspring of diabetic mothers is unknown. In previous clinical and experimental studies, strict metabolic control of the mother has been shown to diminish the risk of fetal maldevelopment, especially if the improved control is initiated in early pregnancy (4-7) or before conception (8).chain amino acids, and creatinine. This suggests that the maternal metabolism of the three major classes of nutrients covariates with the embryonic development in diabetic rat pregnancy. The monitoring of only one of these maternal parameters, e.g. the serum glucose concentration, may therefore not adequately predict the developmental status of the offspring. Our results suggest that the pathogenesis of fetal malformations in diabetic pregnancy is multifactorial. Thus, maintaining metabolites from all nutrient classes at a normal level may be important in preventing adverse fetal outcome. Maintenance of normal serum glucose levels alone, however, does not seem to completely protect the fetus from malformations (9). Other disturbed metabolic processes in the mother, reflected by alterations in serum levels of associated metabolites, may therefore have pathogenic roles in the teratogenicity of diabetic pregnancy. In previous studies of an animal model for diabetic pregnancy, w e found increased rates of fetal malformations and resorptions among the offspring of streptozotocin-diabetic rats

Teratogenic effect of diabetic serum is prevented by supplementation of superoxide dismutase and N-acetylcysteine in rat embryo culture

“…These findings corroborate earlier claims of the multifactorial nature of the teratogenicity of diabetic pregnancy [4,9], and supports the notion of an excess of free oxygen radical activity in the embryos as an integral part of the teratogenic process [10][11][12].…”

“…The mechanisms causing these developmental disturbances are unknown [2,3]. Experimental studies in vivo and in vitro have suggested that glucose and b -hydroxybutyrate cause growth retardation and malformations in rodent embryos [4][5][6]. In an earlier study we showed that serum from insulin-treated diabetic rats is teratogenic despite normalisation of glucose and b -hydroxybutyrate concentrations [7], in line with similar results by Buchanan et al [8].…”

“…The same argument should apply to branched chain amino acids, since a -ketoisocaproic acid (transaminated metabolite of leucine) is able to induce embryonic dysmorphogenesis in vitro [11], but other components are less well characterized. Indirect evidence of a teratogenic effect of increased glucose, b -hydroxybutyrate, branched chain amino acids, and triglyceride concentration was obtained in vivo by multiple linear regression analysis of maternal diabetic serum [4], whereas the importance of folate for in vitro embryonic development has been shown in studies with dialysed serum in culture of embryos [30]. In the present study, the marked simultaneous changes in these factors may, therefore, explain the differences in teratogenicity between N and 50 MD serum.…”

“…In the 50 MD serum, folate concentration was decreased, whereas the branched chain amino acids, triglyceride and b -hydroxybutyrate concentrations were increased in comparison with N serum, all of which have been previously associated with disturbed embryonic development [4,6,11,30,31]. In addition, there were pronounced changes in a number of amino acid concentrations, the significance of which remain to be determined [30,32].…”

Oxidant release is dramatically increased by elevated glucose concentrations in neutrophils from pregnant women

“…Cellular events associated with congenital malformations of offspring occur early in pregnancy. Maternal diabetes in rats and mice has shown impaired embryonic growth at the pre-implantation stage [12] While other diabetesrelated factors such as triglycerides and branched amino acid chains may influence the outcome of pregnancy [13], it has been suggested that the primary teratogen in diabetic pregnancy is hyperglycemia [14][15][16][17]. A number of teratological pathways in embryonic tissue have been identified, including variations in metabolism of inositol, arachidonic acid and reactive oxygen species (ROS) [18][19][20].…”