Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress

Li, Rulin; Chase, Martha; Jung, Sung‐Kwon; Smith, Peter J. S.; Loeken, Mary R.

doi:10.1152/ajpendo.00441.2004

Cited by 101 publications

(119 citation statements)

References 54 publications

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“…Antimycin A is a mitochondrial complex III inhibitor that stimulates superoxide production [40,41] and mimics the effects of maternal diabetes on Pax3 expression and NTD [39,47]. As shown in Fig.…”

Section: Resultsmentioning

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: Resultsmentioning

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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“…Indeed, congenital defects are still more frequent in infants of diabetic mothers than in the general population, in spite of adequate hyperglycaemia control in a large proportion of diabetic pregnant women. Recent reports have observed that the correlation between congenital malformations in infants of diabetic mothers and pre-pregnancy BMI is higher than that between congenital malformations and maternal blood glucose values [92], and that oxidative stress makes an important contribution to the increase in neural tube defects [93]. In addition, obesity and hyperinsulinaemia have been suggested as risk factors for neural tube defects in the general population [94].…”

Section: Relevance and Challenges Aheadmentioning

confidence: 99%

Proinsulin in development: new roles for an ancient prohormone

Hernández‐Sánchez¹,

Mansilla²,

Rosa³

et al. 2006

Diabetologia

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In postnatal organisms, insulin is well known as an essential anabolic hormone responsible for maintaining glucose homeostasis. Its biosynthesis by the pancreatic beta cell has been considered a model of tissue-specific gene expression. However, proinsulin mRNA and protein have been found in embryonic stages before the formation of the pancreatic primordium, and later, in extrapancreatic tissues including the nervous system. Phylogenetic studies have also confirmed that production of insulin-like peptides antecedes the morphogenesis of a pancreas, and that these peptides contribute to normal development. In recent years, other roles for insulin distinct from its metabolic function have emerged also in vertebrates. During embryonic development, insulin acts as a survival factor and is involved in early morphogenesis. These findings are consistent with the observation that, at these stages, the proinsulin gene product remains as the precursor form, proinsulin. Independent of its low metabolic activity, proinsulin stimulates proliferation in developing neuroretina, as well as cell survival and cardiogenesis in early embryos. Insulin/proinsulin levels are finely regulated during development, since an excess of the protein interferes with correct morphogenesis and is deleterious for the embryo. This fine-tuned regulation is achieved by the expression of alternative embryonic proinsulin transcripts that have diminished translational activity.

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“…Thus, discordant expression of various genes may also result in NTDs by diabetes. However, only limited number of genes, such as Pax3 [7,11] and folate binding protein 1 (Folbp1) [12], has been analyzed in these models.…”

mentioning

confidence: 99%

Identification of Genes Differentially Expressed in Mouse Fetuses from Streptozotocin-induced Diabetic Pregnancy by cDNA Subtraction

et al. 2008

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Abstract. Epidemiological studies have shown that the risks of fetal malformation such as neural tube defects increase in diabetic pregnancy. To explore the mechanism of fetal malformation induced by diabetes, cDNA subtraction using mouse embryos (E9.5) of diabetic dams and those of controls was performed to identify differentially expressed genes. The expression level of genes identified by cDNA subtraction was further verified by quantitative RT-PCR using E8.5 embryos, and differential expression of 4 genes, Brcc3, Commd3, Ddx1, and SET was confirmed. We also analyzed the expression level of neural tube defect-related genes, and found that Folbp1, EphrinA5 and Sox10 were differentially expressed. Altered expression of these genes mostly persisted throughout the later stages of the development (E10.5-14.5). Hierarchical clustering analysis showed correlation between expression levels of these genes, suggesting that these genes cooperatively play a role in embryonic development. Our results suggest that an altered gene expression profile in embryos underlies the development of congenital malformation in diabetic pregnancies.

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Hypoxic stress in diabetic pregnancy contributes to impaired embryo gene expression and defective development by inducing oxidative stress

Cited by 101 publications

References 54 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

Proinsulin in development: new roles for an ancient prohormone

Identification of Genes Differentially Expressed in Mouse Fetuses from Streptozotocin-induced Diabetic Pregnancy by cDNA Subtraction

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