Maternal diabetes: An independent risk factor for major cardiovascular malformations with increased mortality of affected infants

Loffredo, Christopher A.; Wilson, P. David; Ferencz, Charlotte

doi:10.1002/tera.1051

Cited by 198 publications

(156 citation statements)

References 34 publications

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“…Maternal diabetes significantly increases the risk of congenital malformations: while rigorous glycaemic control in the periconception period reduces the incidence of congenital malformations, the incidence remains three to fivefold greater than that for non-diabetic pregnancy [1][2][3][4][5]. These malformations arise during the earliest stages of organogenesis, corresponding to approximately weeks 2-8 in human gestation [6].…”

Section: Introductionmentioning

confidence: 99%

Expression of the gene encoding the high-K m glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy

Thorens

Loeken

2007

Diabetologia

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Aims/hypothesis Excess glucose transport to embryos during diabetic pregnancy causes congenital malformations. The early postimplantation embryo expresses the gene encoding the high-K m GLUT2 (also known as SLC2A2) glucose transporter. The hypothesis tested here is that high-K m glucose transport by GLUT2 causes malformations resulting from maternal hyperglycaemia during diabetic pregnancy. Materials and methods Glut2 mRNA was assayed by RT-PCR. The K m of embryo glucose transport was determined by measuring 0.5-20 mmol/l 2-deoxy[ 3 H]glucose transport. To test whether the GLUT2 transporter is required for neural tube defects resulting from maternal hyperglycaemia, Glut2 +/− mice were crossed and transient hyperglycaemia was induced by glucose injection on day 7.5 of pregnancy. Embryos were recovered on day 10.5, and the incidence of neural tube defects in wild-type, Glut2 +/− and Glut2 −/− embryos was scored. Results Early postimplantation embryos expressed Glut2, and expression was unaffected by maternal diabetes. Moreover, glucose transport by these embryos showed Michaelis-Menten kinetics of 16.19 mmol/l, consistent with transport mediated by GLUT2. In pregnancies made hyperglycaemic on day 7.5, neural tube defects were significantly increased in wild-type embryos, but Glut2 +/− embryos were partially protected from neural tube defects, and Glut2 −/− embryos were completely protected from these defects. The frequency of occurrence of wild-type, Glut2 +/− and Glut2 −/− embryos suggests that the presence of Glut2 alleles confers a survival advantage in embryos before day 10.5. Conclusions/interpretations High-K m glucose transport by the GLUT2 glucose transporter during organogenesis is responsible for the embryopathic effects of maternal diabetes.

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Section: Introductionmentioning

confidence: 99%

Expression of the gene encoding the high-K m glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy

Thorens

Loeken

2007

Diabetologia

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“…The excess glucose resulting from maternal diabetes is necessary and sufficient for this effect [25]. While there are likely to be multiple genes whose expression could be affected by maternal diabetes, the similarities between the structural defects seen in homozygous Splotch (Sp/Sp) embryos, which carry loss of function Pax-3 alleles, and defects caused by diabetic pregnancy in humans and animal models (for example, open NTD, affecting closure of the cranial or caudal neuropore, and cardiac outflow tract defects, resulting from defective cardiac neural crest migration [1,5,26,27,28,29]), suggests that Pax-3 deficiency might explain many of the neural tube and neural crest defects associated with diabetic pregnancy. Neural tube and neural crest defects occur with 100% penetrance in Sp/Sp embryos [26], indicating that there are no redundant pathways to compensate for the absence of Pax-3.…”

mentioning

confidence: 99%

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

et al. 2003

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Aims/hypothesis. Maternal diabetes increases oxidative stress in embryos. Maternal diabetes also inhibits expression of embryonic genes, most notably, Pax-3, which is required for neural tube closure. Here we tested the hypothesis that oxidative stress inhibits expression of Pax-3, thereby providing a molecular basis for neural tube defects induced by diabetic pregnancy. Methods. Maternal diabetes-induced oxidative stress was blocked with α-tocopherol (vitamin E), and oxidative stress was induced with the complex III electron transport inhibitor, antimycin A, using pregnant diabetic or non-diabetic mice, primary cultures of neurulating mouse embryo tissues, or differentiating P19 embryonal carcinoma cells. Pax-3 expression was assayed by quantitative RT-PCR, and neural tube defects were scored by visual inspection. Oxidation-induced DNA fragmentation in P19 cells was assayed by electrophoretic analysis.Results. Maternal diabetes inhibited Pax-3 expression and increased neural tube defects, and α-tocopherol blocked these effects. In addition, induction of oxidative stress with antimycin A inhibited Pax-3 expression and increased neural tube defects. In cultured embryo tissues, high glucose-inhibited Pax-3 expression, and this effect was blocked by α-tocopherol and GSHethyl ester, and Pax-3 expression was inhibited by culture with antimycin A. In differentiating P19 cells, antimycin A inhibited Pax-3 induction but did not induce DNA strand breaks. Conclusion/interpretation. Oxidative stress inhibits expression of Pax-3, a gene that is essential for neural tube closure. Impaired expression of essential developmental control genes could be the central mechanism by which neural tube defects occur during diabetic pregnancy, as well as other sources of oxidative stress. [Diabetologia (2003) 46:538-545]

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“…Pregnant women with poorly controlled diabetes risk embryopathies, spontaneous abortion and perinatal mortality [5,6] in direct relation to the severity of the diabetes [7]. In recent years, however, clinical management of pregnant diabetic women has improved markedly and the rate of most complications stemming from diabetic pregnancy has declined in developed countries [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, despite good glycemic control and folic acid supplementation, the rates of congenital malformation, macrosomia and preeclampsia remain higher in pregnant diabetic women than in the general population [1,9,11]. Cellular events associated with congenital malformations of offspring occur early in pregnancy.…”

Section: Introductionmentioning

confidence: 99%

“…Several authors have suggested that diabetes is associated with oxidative stress and ROS [9,[21][22][23][24][25][26][27]. Increased ROS generation has been found in diabetic rats [28], and it has been determined that there is excessive oxidative stress in pregnancies complicated by diabetes [5], which may be lessened by anti-oxidants [29][30][31][32].…”

Section: Introductionmentioning

confidence: 99%

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

Petty

Kindzelskii

Chaiworapongsa

et al. 2005

The Journal of Maternal-Fetal & Neonatal Medicine

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Objective. To evaluate the mechanism of oxidative stress at glucose levels accompanying diabetic pregnancy. Specifically, we hypothesize that elevated glucose overwhelms hexose monophosphate shunt (HMS) down-regulation observed during pregnancy. Methods. Peripheral blood cells from normal healthy pregnant women were exposed to heightened glucose levels to provide an in vitro model of the effects of diabetic pregnancy. Changes in NAD(P)H, reactive oxygen species (ROS) and nitric oxide (NO) production were evaluated in single cells. Results. Altered metabolic dynamics, as judged by NAD(P)H autofluorescence of neutrophils from both pregnant and nonpregnant women, were observed during incubation with 14 mM glucose, a pathophysiologic level. In parallel, increased production of ROS and NO was observed. The ROS and NO levels attained in cells from pregnant women were greater than those observed in cells from non-pregnant women. Inhibitors of the HMS and NAD(P)H oxidase blocked these effects. These metabolic and oxidant changes required approximately one minute, suggesting that transient glucose spikes during pregnancy could trigger this response. Conclusions. Elevated glucose levels enhance HMS activity and oxidant production in cells from pregnant women. This mechanism may be generally applicable in understanding the role of diabetes in materno-fetal health.

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Maternal diabetes: An independent risk factor for major cardiovascular malformations with increased mortality of affected infants

Abstract: The evidence of diabetes-induced major cardiac defects is of urgent clinical significance. The effectiveness of early preconceptional care in the prevention of congenital anomalies has been demonstrated repeatedly.

Cited by 198 publications

References 34 publications

Expression of the gene encoding the high-K m glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy

Expression of the gene encoding the high-K m glucose transporter 2 by the early postimplantation mouse embryo is essential for neural tube defects associated with diabetic embryopathy

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

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

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