Combined supplementation of folic acid and vitamin E diminishes diabetes‐induced embryotoxicity in rats

Gäreskog, Mattias; Eriksson, Ulf J.; Wentzel, Parri

doi:10.1002/bdra.20278

Cited by 43 publications

(35 citation statements)

References 54 publications

(47 reference statements)

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“…Nevertheless, it is worth noting that our data implicate a regulatory role of NF-κB on diabetes-induced apoptotic stimuli. These data were confirmed by a recent study, in which the increased incidence of malformations was associated with a decreased NF-κB activity in embryos of STZ-induced diabetic rats [85].…”

Section: Possible Mechanisms Underlying the Tnfα-regulated Response Tsupporting

confidence: 79%

TNFalpha in the Pathogenesis of Diabetes-Induced Embryopathies: Functions and Targets

Torchinsky¹,

Toder²

2007

Rev Diabet Stud

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■ AbstractHyperglycemia-induced increase in the production of reactive oxygen species (ROS) is proposed to be an initial step in the pathogenesis of diabetes-induced spontaneous abortions and structural inborn anomalies. However, the subsequent steps in this process are incompletely understood. One of the key molecules involved is tumor necrosis factor-alpha (TNFα): its expression is regulated by ROS and it regulates ROS production in turn. This cytokine has been the focus of many studies addressing the mechanisms of different forms of diabetes-induced embryopathies, such as early pregnancy loss, inborn anomalies, fetal growth retardation as well as some pathologies appearing during adult life. In this review, we analyze the results of these studies and discuss how TNFα may regulate the response of pre-and postimplantation stage embryos to diabetes-induced detrimental stimuli. The data presented in this review suggest that TNFα may play a dual role in the pathogenesis of diabetes-induced embryopathies. It may act both as a mediator of diabetesinduced embryotoxic stimuli leading to the death of periimplantation stage embryos and, possibly, as a suppressor of diabetes-induced apoptosis in post-implantation stage embryos. It also appears that TNFα fulfills these functions via interaction with leukemia inhibitory factor (LIF) and the transcription factor NF-κB. These molecules are presently considered as attractive targets for the treatment of diabetesinduced complications. Therefore, further studies addressing their role in the mechanisms underlying diabetes-induced embryopathies are needed to evaluate the safety of such therapies for diabetic women of childbearing age.

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Section: Possible Mechanisms Underlying the Tnfα-regulated Response Tsupporting

confidence: 79%

TNFalpha in the Pathogenesis of Diabetes-Induced Embryopathies: Functions and Targets

Torchinsky¹,

Toder²

2007

Rev Diabet Stud

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“…As oxidative stress is a likely teratogenic mediator of maternal hyperglycemia in DM (see 'Mechanisms of Teratogenesis in Maternal Diabetes'), it is expected that preconception assumption of various antioxidant micronutrients can reduce the risk of malformations in diabetic pregnancies. Various studies confirm that the assumption of specific antioxidant substances, such as ␣ -lipoic acid [Sugimura et al, 2009], vitamin E [Cederberg et al, 2001;Gäreskog et al, 2006] and vitamin C [Cederberg et al, 2001], increases the chance of good prenatal outcome in the offspring of diabetic mothers. Therefore, in the near future, supplementation with multivitamins and fatty acids may become a further widely accepted resource for diabetic mothers [Reece, 2012].…”

Section: Principles Of Preventionmentioning

confidence: 95%

Diabetic Embryopathy: A Developmental Perspective from Fertilization to Adulthood

Castori¹

2012

Mol Syndromol

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Maternal diabetes mellitus is one of the strongest human teratogens. Despite recent advances in the fields of clinical embryology, experimental teratology and preventive medicine, diabetes-related perturbations of the maternofetal unit maintain a considerable impact on the Healthcare System. Classic consequences of prenatal exposure to hyperglycemia encompass (early) spontaneous abortions, perinatal death and malformations. The spectrum of related malformations comprises some recurrent blastogenic monotopic patterns, i.e. holoprosencephaly, caudal dysgenesis and oculoauriculovertebral spectrum, as well as pleiotropic syndromes, i.e. femoral hypoplasia-unusual face syndrome. Despite this, most malformed fetuses display multiple blastogenic defects of the VACTERL type, whose (apparently) casual combination preclude recognizing recurrent patterns, but accurately testifies to their developmental stage at onset. With the application of developmental biology in modern medicine, the effects of diabetes on the unborn patient are expanded to include the predisposition to develop insulin resistance in adulthood. The mechanisms underlying the transgenerational correlation between maternal diabetes and proneness to adult disorders in the offspring remain unclear, and the epigenetic plasticity may represent the missing link. In this scenario, a development-driven summary of the multifaced consequences of maternal diabetes on fertility and child health may add a practical resource to the repertoire of available information on early stages of embryogenesis.

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“…In addition, we found that combined supplementation of two compounds with antioxidative features (folic acid and vitamin E) to pregnant diabetic rats diminished diabetes-induced dysmorphogenesis. The beneficial effects of this combined treatment were associated with normalization of apoptotic-associated protein levels (Gareskog et al 2006).…”

Section: Introductionmentioning

confidence: 93%

N-Acetylcysteine and α-cyano-4-hydroxycinnamic acid alter protein kinase C (PKC)-δ and PKC-ζ and diminish dysmorphogenesis in rat embryos cultured with high glucose in vitro

Gäreskog

Wentzel

2007

Journal of Endocrinology

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Malformations and growth disturbances are two-to threefold more common in infants of diabetic mothers than in offspring of non-diabetic pregnancy. Several suggestions have emerged to explain the reasons for diabetic embryopathy, including enhanced mitochondrial production of reactive oxygen species leading to altered activation of protein kinase C. This study aimed to evaluate the effect of a-cyano-4-hydroxycinnamic acid (CHC) and N-acetylcysteine (NAC) addition on morphology and activity of protein kinase C-d and protein kinase C-z in rat embryos exposed to a high glucose concentration in vitro. Day 9 embryos from normal rats were cultured in 10 or 30 mM glucose concentrations with or without supplementation of CHC, NAC, or protein kinase C inhibitors specific for protein kinase C-d and protein kinase C-z. Embryos were evaluated for malformations, crown rump length, and somite number. Protein kinase C-d and protein kinase C-z activities were estimated by western blot by separating membranous and cytosolic fractions of the embryo. We found increased malformations and growth retardation in embryos cultured in high versus low glucose concentrations. These abnormalities were diminished when CHC and NAC or specific protein kinase C-inhibitors were added to the culture medium. The activities of embryonic protein kinase C-d and protein kinase C-z were increased in the high glucose environment after 24-h culture, but were normalized by the addition of CHC and NAC as well as respective inhibitor to the culture medium. These findings suggest that mitochondrial overproduction of reactive oxygen species is involved in diabetic embryopathy. Furthermore, such overproduction may affect embryonic development, at least partly, by enhancing the activities of protein kinase C-d and protein kinase C-z.

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Combined supplementation of folic acid and vitamin E diminishes diabetes‐induced embryotoxicity in rats

Cited by 43 publications

References 54 publications

TNFalpha in the Pathogenesis of Diabetes-Induced Embryopathies: Functions and Targets

TNFalpha in the Pathogenesis of Diabetes-Induced Embryopathies: Functions and Targets

Diabetic Embryopathy: A Developmental Perspective from Fertilization to Adulthood

N-Acetylcysteine and α-cyano-4-hydroxycinnamic acid alter protein kinase C (PKC)-δ and PKC-ζ and diminish dysmorphogenesis in rat embryos cultured with high glucose in vitro

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