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Maternal diabetes mellitus is associated with increased teratogenesis, which can occur in pregestational type 1 and type 2 diabetes. Cardiac defects and with neural tube defects are the most common malformations observed in fetuses of pregestational diabetic mothers. The exact mechanism by which diabetes exerts its teratogenic effects and induces embryonic malformations is unclear. Whereas the sequelae of maternal pregestational diabetes, such as modulating insulin levels, altered fat levels, and increased reactive oxygen species, may play a role in fetal damage during diabetic pregnancy, hyperglycemia is thought to be the primary teratogen, causing particularly adverse effects on cardiovascular development. Fetal cardiac defects are associated with raised maternal glycosylated hemoglobin levels and are up to five times more likely in infants of mothers with pregestational diabetes compared with those without diabetes. The resulting anomalies are varied and include transposition of the great arteries, mitral and pulmonary atresia, double outlet of the right ventricle, tetralogy of Fallot, and fetal cardiomyopathy.A wide variety of rodent models have been used to study diabetic teratogenesis. Both genetic and chemically induced models of type 1 and 2 diabetes have been used to examine the effects of hyperglycemia on fetal development. Factors such as genetic background as well as confounding variables such as obesity appear to influence the severity of fetal abnormalities in mice. In this review, we will summarize recent data on fetal cardiac effects from human pregestational diabetic mothers, as well as the most relevant findings in rodent models of diabetic cardiac teratogenesis.
Birth Defects Res A Clin Mol Teratol 2009 Jun
PMID:Fetal cardiac effects of maternal hyperglycemia during pregnancy. 1918 Jun 50

Maternal diabetes mellitus is one of the strongest human teratogens. Despite recent advances in the fields of clinical embryology, experimental teratology and preventive medicine, diabetes-related perturbations of the maternofetal unit maintain a considerable impact on the Healthcare System. Classic consequences of prenatal exposure to hyperglycemia encompass (early) spontaneous abortions, perinatal death and malformations. The spectrum of related malformations comprises some recurrent blastogenic monotopic patterns, i.e. holoprosencephaly, caudal dysgenesis and oculoauriculovertebral spectrum, as well as pleiotropic syndromes, i.e. femoral hypoplasia-unusual face syndrome. Despite this, most malformed fetuses display multiple blastogenic defects of the VACTERL type, whose (apparently) casual combination preclude recognizing recurrent patterns, but accurately testifies to their developmental stage at onset. With the application of developmental biology in modern medicine, the effects of diabetes on the unborn patient are expanded to include the predisposition to develop insulin resistance in adulthood. The mechanisms underlying the transgenerational correlation between maternal diabetes and proneness to adult disorders in the offspring remain unclear, and the epigenetic plasticity may represent the missing link. In this scenario, a development-driven summary of the multifaced consequences of maternal diabetes on fertility and child health may add a practical resource to the repertoire of available information on early stages of embryogenesis.
Mol Syndromol 2013 Feb
PMID:Diabetic embryopathy: a developmental perspective from fertilization to adulthood. 2365 78

Metabolic disorders of the mother adversely affect early embryo development, causing changes in maternal metabolism and consequent alterations in the embryo environment in the uterus. The goal of this study was to analyse the biochemical profiles of embryonic fluids and blood plasma of rabbits with and without insulin-dependent diabetes mellitus (DT1), to identify metabolic changes associated with maternal diabetes mellitus in early pregnancy. Insulin-dependent diabetes was induced by alloxan treatment in female rabbits 10 days before mating. On day 6 post-coitum, plasma and blastocoel fluid (BF) were analysed by ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) (Metabolon Inc. Durham, NC, USA). Metabolic datasets comprised a total of 284 and 597 compounds of known identity in BF and plasma, respectively. Diabetes mellitus had profound effects on maternal and embryonic metabolic profiles, with almost half of the metabolites changed. As predicted, we observed an increase in glucose and a decrease in 1,5-anhydroglucitol in diabetic plasma samples. In plasma, fructose, mannose, and sorbitol were elevated in the diabetic group, which may be a way of dealing with excess glucose. In BF, metabolites of the pentose metabolism were especially increased, indicating the need for ribose-based compounds relevant to DNA and RNA metabolism at this very early stage of embryo development. Other changes were more consistent between BF and plasma. Both displayed elevated acylcarnitines, body3-hydroxybutyrate, and multiple compounds within the branched chain amino acid metabolism pathway, suggesting that lipid beta-oxidation is occurring at elevated levels in the diabetic group. This study demonstrates that maternal and embryonic metabolism are closely related. Maternal diabetes mellitus profoundly alters the metabolic profile of the preimplantation embryo with changes in all subclasses of metabolites.
Int J Mol Sci 2020 Jan 30
PMID:Metabolic Profiling in Blastocoel Fluid and Blood Plasma of Diabetic Rabbits. 3201 38

During the first days of development the preimplantation embryo is supplied with nutrients from the surrounding milieu. Maternal diabetes mellitus affects the uterine microenvironment, leading to a metabolic adaptation processes in the embryo. We analysed embryonic fatty acid (FA) profiles and expression of processing genes in rabbit blastocysts, separately in embryoblasts (EBs) and trophoblasts (TBs), to determine the potential consequences of maternal diabetes mellitus on intracellular FA metabolism. Insulin-dependent diabetes was induced by alloxan in female rabbits. On Day 6 post coitum, FA profiles in blastocysts (EB, TB and blastocoel fluid) and maternal blood were analysed by gas chromatography. The expression levels of molecules involved in FA elongation (fatty acid elongases, ELOVLs) and desaturation (fatty acid desaturases, FADSs) were measured in EB and TB. Maternal diabetes mellitus influenced the FA profile in maternal plasma and blastocysts. Independent from metabolic changes, rabbit blastocysts contained a higher level of saturated fatty acids (SFAs) and a lower level of polyunsaturated fatty acids (PUFAs) compared to the FA profile of the maternal plasma. Furthermore, the FA profile was altered in the EB and TB, differently. While SFAs (palmitic and stearic acid) were elevated in EB of diabetic rabbits, PUFAs, such as docosahexaenoic acid, were decreased. In contrast, in the TB, lower levels of SFAs and higher levels of oleic acid were observed. EB and TB specific alterations in gene expression were found for ELOVLs and FADSs, key enzymes for FA elongation and desaturation. In conclusion, maternal diabetes mellitus alters embryonic FA metabolism differently in EB and TB, indicating a lineage-specific metabolic adaptive response.
Mol Hum Reprod 2020 11 01
PMID:Embryonic fatty acid metabolism in diabetic pregnancy: the difference between embryoblasts and trophoblasts. 3297 66