Significance of glutathione-dependent antioxidant system in diabetes-induced embryonic malformations.

Sakamaki, Hiroyuki; Akazawa, Shoichi; Ishibashi, Miwa; Izumino, Kiyohiro; Takino, Hirofumi; Yamasaki, Hideki; Yamaguchi, Yukiko; Goto, Shunsuke; Urata, Yoshishige; Kondo, Takahito; Nagataki, Shigenobu

doi:10.2337/diabetes.48.5.1138

Cited by 119 publications

(78 citation statements)

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“…Recently, the deleterious effect of oxidant stress on Pax DNA binding was also demonstrated for Pax3 (56a). The involvement of reactive oxygen species in diabetic embryopathy is supported by studies demonstrating amelioration of congenital malformations with antioxidants (57)(58)(59). Additionally, a rat substrain resistant to dysmorphogenesis produced by maternal diabetes has been shown to have increased levels of both superoxide dismutase and catalase mRNA when compared with a more sensitive substrain (60).…”

Section: Discussionmentioning

confidence: 57%

Diabetic Embryopathy in C57BL/6J Mice

et al. 2001

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Maternal diabetes (types 1 and 2) induces a broad array of congenital malformations, including neural tube defects (NTDs), in humans. One of the difficulties associated with studying diabetic embryopathy is the rarity of individual malformations. In an attempt to develop a sensitive animal model for maternal diabetes-induced NTDs, the present study uses chemically induced diabetes in an inbred mouse model with or without the splotch (Sp) mutation, a putatively nonfunctional allele of Pax3. Pax3 deficiency has been associated with an increase in NTDs. Female C57BL/6J mice, either with or without the Sp allele, were injected intravenously with alloxan (100 mg/kg), and plasma glucose was measured 3 days later. A wide range of hyperglycemia was induced, and these diabetic mice were bred to C57BL/6J males, some carrying the Sp allele. Gestational-day-18 fetuses were examined for developmental malformations. Fetuses from matings in which either parent carried the Sp allele were genotyped by polymerase chain reaction. Maternal diabetes significantly decreased fetal weight and increased the number of resorptions and malformations, including NTDs. A significant correlation was found between the level of maternal hyperglycemia and the malformation rate. The sex ratio for live fetuses in diabetic litters was significantly skewed toward male fetuses. Matings involving the Sp allele yielded litters with significantly higher percentages of maternal diabetes-induced spina bifida aperta but not exencephaly, and this increase was shown to be associated with the presence of a single copy of the Sp allele in affected fetuses. Thus, Pax3 haploinsufficiency in this murine model of diabetic embryopathy is associated with caudal but not cranial NTDs.

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Section: Discussionmentioning

confidence: 57%

Diabetic Embryopathy in C57BL/6J Mice

et al. 2001

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“…The congenital malformations associated with diabetic pregnancy affect many major organs, including the central nervous, cardiovascular, gastrointestinal, urogenital and musculoskeletal systems [5,6]. The pathogenesis of congenital anomalies is complex and still poorly understood, although it has been suggested that excessive reactive oxygen species (ROS) associated with hyperglycaemia are responsible for the increased risk of malformation [7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

et al. 2009

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Aims/hypothesis Maternal diabetes during pregnancy increases the risk of congenital malformations such as neural tube defects (NTDs). Although the mechanism of this effect is uncertain, it is known that levels of nitric oxide synthase (NOS) and nitric oxide are elevated in embryos of a mouse model of diabetes. We postulated that overproduction of nitric oxide causes diabetes-induced congenital malformations and that inhibition of inducible NOS (iNOS) might prevent diabetic embryopathy. Methods Mice were rendered hyperglycaemic by intraperitoneal injection of streptozotocin. The incidence of congenital malformations including NTDs was evaluated on gestational day 18.5. We assessed the involvement of iNOS in diabetesinduced malformation by administering ONO-1714, a specific inhibitor of iNOS, to pregnant mice with streptozotocininduced diabetic mice and by screening mice with iNOS deficiency due to genetic knockout (iNos −/− ). Results ONO-1714 markedly reduced the incidence of congenital anomalies, including NTDs, in fetuses of a mouse model of diabetes. It also prevented apoptosis in the head region of fetuses, indicating that iNOS is involved in diabetesrelated congenital malformations. Indeed, no NTDs were observed in fetuses of diabetic iNos −/− mice and the incidence of other malformations was also markedly reduced. Conclusions/interpretation We conclude that increased iNOS activity during organogenesis plays a crucial role in the pathogenesis of diabetes-induced malformations and suggest that inhibitors of iNOS might help prevent malformations, especially NTDs, in diabetic pregnancy.

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“…Evidence of ROS involvement in hyperglycemia-induced embryopathy was first obtained in studies in which antioxidant enzymes proved to be protective in vitro (18,19). Increased ROS production (20,21) and lipid peroxidation (22) have subsequently been found in rat embryos cultured in high glucose and in embryos of diabetic rat mothers. Enzymatically produced ROS can disturb embryo development in vitro similarly to the effect of high glucose (23), and the resulting maldevelopment can be blocked by vitamins E and C separately (24).…”

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confidence: 99%

Combined Treatment with Vitamin E and Vitamin C Decreases Oxidative Stress and Improves Fetal Outcome in Experimental Diabetic Pregnancy

2001

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The aim was to investigate whether dietary supplementation of a combination of the two antioxidants, vitamin E and vitamin C, would protect the fetus in diabetic rat pregnancy at a lower dose than previously used. Normal and streptozotocin-induced diabetic rats were mated and given standard food or food supplemented with either 0.5% vitamin E ϩ 1% vitamin C or 2% vitamin E ϩ 4% vitamin C. At gestational d 20, gross morphology and weights of fetuses were evaluated. Vitamins E and C and thiobarbituric acid reactive substances were measured in maternal and fetal compartments. In addition, protein carbonylation was estimated in fetal liver. Maternal diabetes increased the rate of malformation and resorption in the offspring. High-dose antioxidant supplementation decreased fetal dysmorphogenesis to near normal levels. The low-dose group showed malformations and resorptions at an intermediate rate between the untreated and the high-dose groups. Thiobarbituric acid reactive substances were increased in fetal livers of diabetic rats and reduced to normal levels already by low-dose antioxidative treatment. Protein carbonylation rate was also increased in fetal liver of diabetic rats; it was normalized by high-dose treatment but only partially reduced by low-dose antioxidants. We conclude that combined antioxidative treatment with vitamins E and C decreases fetal malformation rate and diminishes oxygen radicalrelated tissue damage. However, no synergistic effect between the two antioxidants was noted, a result that may influence future attempts to design antiteratogenic treatments in diabetic pregnancy. Oxidatively modified proteins may be teratogenically important mediators in diabetic embryopathy. Maternal type-1 diabetes during pregnancy causes an increased rate of malformation in the fetus despite insulin treatment and glucose monitoring (1-3). The incidence of fetal malformations in type-1 diabetic pregnancies is estimated to be 5-10% in recent studies (4 -8). Several clinical studies have demonstrated that high maternal HbA1c levels during early pregnancy are associated with an increased risk for malformations (4, 9, 10). It is, however, likely that the pathogenesis of diabetic embryopathy is multifactorial (11), and in experimental work not only maternal serum levels of glucose but also levels of triglycerides, ␤-hydroxybutyrate, branched-chain amino acids, and creatinine correlate positively with increased resorption and malformation rates (12). Also, genetic factors may predispose for the development of malformations in maternal diabetes (13,14).The putative role of ROS in the development of diabetic complications has been investigated for several decades (15-17). Evidence of ROS involvement in hyperglycemia-induced embryopathy was first obtained in studies in which antioxidant enzymes proved to be protective in vitro (18,19). Increased ROS production (20, 21) and lipid peroxidation (22) have subsequently been found in rat embryos cultured in high glucose and in embryos of diabetic rat mothers. Enzymatically prod...

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Significance of glutathione-dependent antioxidant system in diabetes-induced embryonic malformations.

Cited by 119 publications

References 0 publications

Diabetic Embryopathy in C57BL/6J Mice

Diabetic Embryopathy in C57BL/6J Mice

Prevention of neural tube defects by loss of function of inducible nitric oxide synthase in fetuses of a mouse model of streptozotocin-induced diabetes

Combined Treatment with Vitamin E and Vitamin C Decreases Oxidative Stress and Improves Fetal Outcome in Experimental Diabetic Pregnancy

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