Effects of hyperglycaemia on sorbitol and myo-inositol contents of cultured embryos: treatment with aldose reductase inhibitor and myo-inositol supplementation

Hashimoto, Masao; Akazawa, Shoichi; Akazawa, M.; Akashi, M; Yamamoto, Hisako; Maeda, Yasuo; Yamaguchi, Yoshihiko; Yamasaki, Hironori; Tahara, Daigo; Nakanishi, Tomohiro

doi:10.1007/bf00400203

Cited by 70 publications

(44 citation statements)

References 41 publications

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“…Homocysteine has been reported to be embryo-toxic during the process of neural tube formation [40][41][42] and is known to increase the reactive oxygen species (ROS) [43]. Although the mechanism of diabetes-induced congenital defects remains unclear, an excess of ROS, increased somatomedin inhibitor, myo-inositol deficiency, increased lipid peroxidation, arachidonic acid deficiency, and altered prostaglandin have been reported to be involved in the pathogenesis of diabetes-induced embryopathy [24,38,[44][45][46]. Especially, the excess of ROS is thought to be particularly important.…”

Section: Discussionmentioning

confidence: 99%

Folic Acid Prevents Congenital Malformations in the Offspring of Diabetic Mice

et al. 2009

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Abstract. It is well known that maternal diabetes causes various congenital malformations. Although there are many reports that folic acid (FA) administration in pregnancy reduces the risk of birth defects including neural tube defects (NTDs), a precise analysis on the preventive effect of FA against diabetic embryopathy has not been done yet. In this study, we analyzed the preventive effects of FA on congenital malformations including NTDs, cardiovascular, and skeletal malformations using a diabetic mouse model. Female mice were rendered hyperglycemic by streptozotocin and then mated. Pregnant diabetic mice were treated daily with FA (3 mg/kg body weight) or saline between gestational days (GD) 6 and 10. On GD 18, fetuses were examined for congenital malformations. FA did not affect plasma glucose levels. In the DM control group, the incidence of NTDs, cardiovascular, and skeletal malformations was 28.4%, 28.5%, and 29.7%, respectively. In the FA-treated group, the corresponding proportions reduced to 6.0%, 2.5% and 12.5%, respectively. A whole-mount TUNEL revealed an increased apoptosis in the hindbrain region of embryos from DM control group on day 9.5, and the apoptosis was decreased by FA treatment. Maternal plasma homocysteine levels on GD 9.5 were significantly lowered in DM control group compared with those in non-DM group, and FA treatment did not show a significant effect. These results indicate that FA is effective for the prevention of various diabetic embryopathy including NTDs, cardiovascular, and skeletal malformations, and suggested that this effect is independent from homocysteine metabolism and possibly mediated by decreasing the abnormal apoptosis during organogenesis.

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Section: Discussionmentioning

confidence: 99%

Folic Acid Prevents Congenital Malformations in the Offspring of Diabetic Mice

et al. 2009

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“…Although several teratogenic factors such as sorbitol accumulation [51], myo-inositol deficiency [19], arachidonic acid deficiency [18], altered prostaglandin metabolism [52] and increased concentration of 3-deoxyglucosone [53] are altered in embryos of diabetic pregnancy, the mechanisms by which these abnormalities lead to dysmorphogenesis have not been determined. Only recently, it has been shown that oxidative stress induced by maternal diabetes could lead to neural tube defects by impairing the expression of genes that control developmental processes [23].…”

Section: Discussionmentioning

confidence: 99%

“…abolic abnormalities including increased superoxide dismutase activity [15,16,17], reduced concentrations of myoinositol and arachidonic acid [18,19] and inhibition of the pentose phosphate shunt pathway [20]. Moreover, the frequency of embryonic malformations in diabetic pregnancy has been reported to be reduced by dietary supplements of antioxidants such as vitamin E or vitamin C [16,21,22,23] and butylated hydroxytoluene [24], suggesting that oxidative stress is involved in embryonic dysmorphogenesis.…”

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confidence: 99%

Altered gene expression with abnormal patterning of the telencephalon in embryos of diabetic Albino Swiss mice

Liao

Tay

et al. 2004

Diabetologia

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Aims/hypothesis. Several studies have shown that maternal diabetes increases the risk of congenital malformations in various organ systems including the neural tube. The present study analysed molecular and morphological changes in the forebrain of embryos from diabetic Albino Swiss mice. Methods. Maternal diabetes-induced morphological changes in the forebrain were examined histologically. Cell proliferation index was assayed by BrdU labelling. In situ hybridisation and quantitative real-time PCR were used to analyse the expression of genes coding for sonic hedgehog (Shh), Nkx2.1, brain factor-1 (BF-1) and bone morphogenetic protein-4 (Bmp4) that control forebrain patterning.Results. There were no distinguishable abnormalities in the forebrain of embryos from diabetic pregnancies on embryonic day 0.5. At embryonic day 11.5, embryos of diabetic pregnancies displayed a fusion and thickening of the ventral telencephalic neuroepithelium and a partial absence of the dorsal telencephalon, indicating a severe patterning defect in the dorsoventral axis of the telencephalon. The cell proliferation index was also higher in the ventral telencephalon of these embryos. Molecular analyses indicated that expression of Shh, Nkx2.1 and BF-1 was increased and their expression domains expanded dorsally in the ventral telencephalon in embryos of diabetic mice at embryonic day 11.5. The expression of Bmp4 was reduced in the dorsal forebrain of these embryos. At embryonic day 8.5, only Shh expression was increased. Conclusions/interpretation. Altered expression of various genes involved in dorsoventral patterning of the forebrain is associated with forebrain malformations in embryos of diabetic mice. [Diabetologia (2004) 47:523-531]

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“…For example, sorbitol formation is enhanced in embryos sub- jected to a diabetic environment in vivo (52) and in vitro (53). However, attempts to block dysmorphogenesis by inhibiting aldose reductase have not been particularly successful (52)(53)(54). Evidence in favor of enhanced hexosamine pathway activity has been found in embryos of diabetic mice (55) as well as in the enhanced formation of the reactive glycosylating agent deoxyglucosone (56) in embryos subjected to high glucose concentration.…”

Section: Discussionmentioning

confidence: 99%

Maternal Diabetes In Vivo and High Glucose In Vitro Diminish GAPDH Activity in Rat Embryos

2003

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The aim of the present study was to investigate whether diabetic embryopathy may be associated with the inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) resulting from an excess of reactive oxygen species (ROS) in the embryo. Recent demonstrations of enhanced ROS production in mitochondria of bovine aortic endothelial cells exposed to high glucose have supported the idea that the pathogenesis of diabetic complications may involve ROS-induced GAPDH inhibition. We investigated whether a teratogenic diabetic environment also inhibits embryonic GAPDH activity and alters GAPDH gene expression and whether antioxidants diminish such GAPDH inhibition. In addition, we determined whether the inhibition of GAPDH with iodoacetate induces dysmorphogenesis, analogous to that caused by high glucose concentration, and whether antioxidants modulated the putative teratogenic effect of such direct GAPDH inhibition. We found that embryos from diabetic rats and embryos cultured in high glucose concentrations showed decreased activity of GAPDH (by 40 -60%) and severe dysmorphogenesis on gestational days 10.5 and 11.5. GAPDH mRNA was decreased in embryos of diabetic rats compared to control embryos. Supplementing the high-glucose culture with the antioxidant N-acetylcysteine (NAC) increased GAPDH activity and diminished embryonic dysmorphogenesis. Embryos cultured with iodoacetate showed both decreased GAPDH activity and dysmorphogenesis; supplementing the culture with NAC increased both parameters toward normal values. In conclusion, dysmorphogenesis caused by maternal diabetes is correlated with ROS-induced inhibition of GAPDH in embryos, which could indicate that inhibition of GAPDH plays a causal role in diabetic embryopathy. Diabetes

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Effects of hyperglycaemia on sorbitol and myo-inositol contents of cultured embryos: treatment with aldose reductase inhibitor and myo-inositol supplementation

Cited by 70 publications

References 41 publications

Folic Acid Prevents Congenital Malformations in the Offspring of Diabetic Mice

Folic Acid Prevents Congenital Malformations in the Offspring of Diabetic Mice

Altered gene expression with abnormal patterning of the telencephalon in embryos of diabetic Albino Swiss mice

Maternal Diabetes In Vivo and High Glucose In Vitro Diminish GAPDH Activity in Rat Embryos

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