Diabetic Teratogenesis: In Vitro Evidence for a Multifactorial Etiology With Little Contribution From Glucose Per Se

Abstract

To determine the extent to which elevated glucose and 3-hydroxybutyrate (3OHB) concentrations contribute to the embryotoxic properties of diabetic serum, we tested the effects of serum from untreated or acutely insulin-treated diabetic rats on the development of mouse embryos during neurulation in vitro. Male Sprague-Dawley rats (n = 143) with streptozocin-induced diabetes for 1 week received infusions of insulin (n = 105) or saline (n = 38) for up to 120 min. The insulin-infused animals were exsanguinated when serum glucose concentrations fell to between 5.6 and 8.3 mM. Saline-infused animals were exsanguinated after a similar duration of infusion. Serum samples were tested for embryotoxic effects on 3-6 somite mouse embryos cultured in vitro for 24 h. Of embryos cultured in serum from untreated diabetic animals (glucose: 24 +/- 1 mM; 3OHB: 2.0 +/- 0.3 mM), 36% (31 of 87) exhibited gross malformations, mostly of the neural tube. Only 16% (10 of 62) of embryos grown in serum from acutely insulin-treated animals (glucose: 7.4 +/- 0.2 mM; 3OHB: 0.20 +/- 0.06 mM) were malformed. This rate that was less than half the rate caused by exposure to diabetic serum (P < 0.01), but a rate that remained much greater than the rate associated with culture in normal serum (0% in this study; < 2% historically). In vitro addition of glucose to serum from insulin-treated animals to re-establish hyperglycemia in the diabetic range (25 mM) resulted in a 17% (12 of 70) malformation rate, nearly identical to the 16% rate caused by normoglycemic serum from insulin-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

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

“…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]. These studies support the notion of a multifactorial aetiology of embryonic dysmorphogenesis in diabetic pregnancy [9,10].…”

“…On the other hand, culturing embryos in the same glucose concentration (30 mmol/l) in diabetic (50 MD) serum yielded further decreased embryonic size compared with culture in normal serum. This finding indicates the presence of teratogenic components in diabetic serum other than the high glucose concentration [7,8].…”

Maternal diabetes in the rat impairs the formation of neural-crest derived cranial nerve ganglia in the offspring

“…These data suggest similarities between the teratogenic actions of several specific teratogenic substances and maternal diabetes mellitus. The mechanisms for diabetic teratogenicity are perhaps the least well understood, probably due to the multitude of interacting teratogenic substances in diabetes mellitus [40,41,42]. Further insight in the teratogenic actions of maternal diabetes could therefore also cross-fertilise the understanding of other teratogens.…”

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

“…Thus, the transaminated product of leucine, a-keto-isocaproic acid, is teratogenic in rat embryo culture at a concentration as low as 3 mmol/L (23). In a recent study, Buchanan et al (48) reported that the teratogenic potential of serum from diabetic rats was dependent on other factors in addition to the elevated levels of glucose. The experimental finding of the teratologic potential of diabetes-associated metabolites, in addition to glucose, agrees…”