Diabetes in Pregnancy: Uterine Blood Flow and Embryonic Development in the Rat

Wentzel, Parri; Jansson, Leif; Eriksson, Ulf J.

doi:10.1203/00006450-199510000-00021

Cited by 24 publications

(11 citation statements)

References 21 publications

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“…It can be speculated that radicals are formed within the embryonic mitochondria, since they are subjected to substrate overload in the diabetic environment. In favor of this hypothesis are the facts that diabetes induces increased uterine blood flow in early rat pregnancy (50), GLUT-1 is not 4. A schematic figure of the rat catalase promoter region (A) and cDNA (B), outlining the differences in DNA sequence between the H a n d U strains.…”

Section: T I N 5 -C T G a C C G A G C T G G C Ta C 5 -C C T G C T Tmentioning

confidence: 79%

Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain.

et al. 2000

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Previous studies have suggested that reactive oxygen species (ROS) are mediators in the teratogenic process of diabetic pregnancy. In an animal model for diabetic p r e g n a n c y, offspring of the H rat strain show minor dysmorphogenesis when the mother is diabetic, whereas the offspring of diabetic rats of a sister strain, U, display major morphologic malformations. Earlier studies have shown that embryonic catalase activity is higher in the H than in the U strain, and maternal diabetes increases this difference in activity. The aim of this study was to characterize the influence of genetic predisposition on diabetic embryopathy by comparing the mRNA levels of ROS-metabolizing enzymes in the two strains. We determined the mRNA levels of catalase, glutathione peroxidase, -g l u t a m y l c y s t e i n -s y n t h e t a s e , glutathione reductase, and superoxide dismutase (CuZn-SOD and Mn-SOD) in day 11 embryos of normal and diabetic H and U rats using semiquantitative reverse transcription-polymerase chain reaction. The mRNA levels of catalase and Mn-SOD were increased in H embryos as a response to maternal diabetes, and no d i fferences were found for the other genes. Sequence analysis of the catalase promoter indicated that the d i fference in mRNA levels may result from diff e r e n t regulation of transcription. Sequence analysis of the catalase cDNA revealed no differences between the two strains in the translated region, suggesting that the previously observed difference in the electrophoretic mobility in zymograms is due to posttranslational modifications. An impaired expression of scavenging enzymes in response to ROS excess can thus be an integral part of a genetic predisposition to embryonic dysmorphogenesis. D i a b e t e s 4 9 :1 0 1-107, 2000 M aternal type 1 diabetes during pregnancy has been known for many years to be associated with an increased risk for congenital malformations in the offspring (1-4). Clinical studies have estimated the risk for a malformed fetus in a t y p e 1 diabetic pregnancy to be in the range of 5-10% (5-9). The malformations are induced before the 7th postconceptional week in human diabetic pregnancy (10). In rats, the teratogenic process is believed to occur during organogenesis (11). Recent reports, however, indicate that a diabetic environment may decrease the inner cell mass (12) and that a high glucose concentration can lead to increased apoptosis already in the preimplantation embryo (13). The teratogenic process and its predisposing factors are not known in detail. In pregnancies with poorly controlled diabetes, however, there is a correlation between the level of H b A 1 c in maternal blood and the risk for having a malformed child (5,14,15).The hypothesis has been put forward that an excess of reactive oxygen species (ROS) mediates the teratogenicity of diabetic pregnancy (16)(17)(18)(19). The oxygen radicals may be harmful to the cell and its functions by reacting with unsaturated fatty acids in membranes, yielding lipid peroxides and causing decreased membran...

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Section: T I N 5 -C T G a C C G A G C T G G C Ta C 5 -C C T G C T Tmentioning

confidence: 79%

Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain.

et al. 2000

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“…Congenital malformations are induced in early diabetic pregnancy, usually before the 7th gestational week in humans (5). Analysis of the preplacenta (yolk sac) or early placenta in diabetic rats shows an increased blood flow in the uterine and decidual tissues compared with normal pregnant rats (31), thus suggesting that the transfer of compounds between mother and embryo during a teratologically important period of pregnancy may be elevated. We found that the rate of downregulation of Wnt-3a is related to the dose of exogenous RA, and embryos of severely diabetic mice treated with 50 mg/kg RA downregulated Wnt-3a at a rate similar to embryos of nondiabetic mice treated with 100 mg/kg RA.…”

Section: Discussionmentioning

confidence: 99%

Maternal Diabetes Increases the Risk of Caudal Regression Caused by Retinoic Acid

Chan

Koide

et al. 2002

Diabetes

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Maternal diabetes increases the risk of congenital malformations in the offspring of affected pregnancies. This increase arises from the teratogenic effect of the maternal diabetic milieu on the developing embryo, although the mechanism of this action is poorly understood. In the present study, we examined whether the vitamin A metabolite retinoic acid (RA), a common drug with well-known teratogenic properties, may interact with maternal diabetes to alter the incidence of congenital malformations in mice. Our results show that when treated with RA, embryos of diabetic mice are significantly more prone than embryos of nondiabetic mice to develop caudal regression, a defect that is highly associated with diabetic pregnancy in humans. By studying the vestigial tail (Wnt-3a vt ) mutant, we provide evidence that Wnt-3a, a gene that controls the development of the caudal region, is directly involved in the pathogenic pathway of RA-induced caudal regression. We further show that the molecular basis of the increased susceptibility of embryos of diabetic mice to RA involves enhanced downregulation of Wnt-3a expression. This positive interaction between RA and maternal diabetes may have implications for humans in suggesting increased susceptibility to environmental teratogens during diabetic pregnancy. Diabetes 51:2811-2816, 2002

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“…Blood flow to the uterine and decidual tissues is increased during the early stages of pregnancy in diabetic rats [19], suggesting that retinoic acid could be delivered to developing embryos at an increased concentration under conditions of hyperglycaemia. Retinoic acid in the embryo is synthesised from vitamin A (retinol) obtained from the maternal circulation.…”

Section: Discussionmentioning

confidence: 99%

Hyperglycaemia potentiates the teratogenicity of retinoic acid in diabetic pregnancy in mice

et al. 2004

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Aims/hypothesis. We recently showed in mice that maternal diabetes increases embryonic susceptibility to caudal regression induced by vitamin A metabolite retinoic acid. Here we tested whether in the maternal diabetic milieu hyperglycaemia is the critical factor responsible for mediating this increased susceptibility. Methods. Non-diabetic pregnant mice were made hyperglycaemic by subcutaneous injections of glucose at regular intervals. Conversely, diabetic pregnant mice were treated with phlorizin to induce renal glucosuria and thus reduce blood glucose concentrations. Pregnant mice were treated with retinoic acid and the extent of caudal regression in mouse embryos, measured in terms of the ratio of tail length to crown-rump length was assessed. Embryos were also examined for Wnt-3a expression and cell death. Results. Embryos of mice treated with glucose had a greater extent of caudal regression induced by retinoic acid than saline-treated controls, with enhanced downregulation of Wnt-3a expression and exacerbated cell death specifically at the caudal end of the embryo. Embryos of diabetic mice treated with phlorizin had a similar extent of caudal regression to embryos of nondiabetic mice after treatment with retinoic acid. Conclusions/interpretation. Hyperglycaemia increases embryonic susceptibility to caudal regression induced by retinoic acid, with the underlying cellular and molecular changes closely mimicking those that occur in maternal diabetes. Reduction of blood glucose concentrations in diabetic mice completely abolishes this increased susceptibility to retinoic acid. These results suggest that in maternal diabetes hyperglycaemia is the critical factor responsible for potentiating the teratogenic effect of retinoic acid. [Diabetologia (2004) 47:515-522]

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Diabetes in Pregnancy: Uterine Blood Flow and Embryonic Development in the Rat

Cited by 24 publications

References 21 publications

Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain.

Increased mRNA levels of Mn-SOD and catalase in embryos of diabetic rats from a malformation-resistant strain.

Maternal Diabetes Increases the Risk of Caudal Regression Caused by Retinoic Acid

Hyperglycaemia potentiates the teratogenicity of retinoic acid in diabetic pregnancy in mice

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