Advances in Understanding the Molecular Causes of Diabetes-Induced Birth Defects

Loeken, Mary R.

doi:10.1016/j.jsgi.2005.09.007

Cited by 91 publications

(81 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, hyperglycaemia induces apoptosis in early organogenesis in pre-and post-implantation rodent embryos through cell-death effector pathways [25][26][27][28][29]. Also, neural tube defects (NTDs) are associated with apoptosis in the offspring of diabetic mice [30,31]. Taken together, these findings support the assumption that diabetes-induced inappropriate apoptosis in embryos might lead to NTDs.…”

Section: Introductionmentioning

confidence: 52%

“…In addition, diabetes-induced inappropriate apoptosis in embryos during neurulation has been demonstrated to be one of the mechanisms leading to neural tube defects [31]. We therefore assayed apoptosis in the embryos of DM and non-DM, WT or TRX-Tg mice during organogenesis, by histochemical analysis of apoptotic cells and cleaved caspase-3.…”

Section: Discussionmentioning

confidence: 99%

“…Diabetes was treated with subcutaneously implanted insulin pellets (Linshin, Scarborough, ON, Canada) that continuously release insulin. The insulin pellets controlled the diabetes to the extent that the mice gained weight and ovulated normally [30,31]. Approximately 2-3 weeks after implantation of the insulin pellets, mice became hyperglycaemic, at which time they were mated with heterozygous TRX-Tg males.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

et al. 2010

View full text Add to dashboard Cite

Aims/hypothesis Experimental studies have suggested that apoptosis is involved in diabetic embryopathy through oxidative stress. However, the precise mechanism of diabetic embryopathy is not yet clear. Thioredoxin (TRX) is a small, ubiquitous, multifunctional protein, which has recently been shown to protect cells from oxidative stress and apoptosis. Using transgenic mice that overproduce human TRX-1 (TRX-Tg mice), we examined whether oxidative stress is involved in fetal dysmorphogenesis in diabetic pregnancies. Methods Non-diabetic and streptozotocin-induced diabetic (DM) female mice were mated with male TRX-Tg mice. Pregnant mice were killed either at day 10 or day 17 of gestation, and viable fetuses and their placentas were recovered, weighed and assessed for gross and histological morphology, biochemical markers and gene expression. Results In both wild-type (WT) and transgenic (Tg) groups, fetal and placental weights in the diabetic group were significantly decreased compared with the non-diabetic group. The incidence of malformation was higher in the diabetic group, and was significantly decreased in the TRXTg group (DM-WT vs DM-Tg; 28.6% vs 10.4%). Oxidative stress markers such as thiobarbituric acid reactive substances and 8-hydroxy-2′-deoxyguanosine were increased in DM-WT group fetuses but were decreased in fetuses from the DM-Tg group. Furthermore, immunohistochemically assayed apoptosis and cleaved caspase-3 production in embryonic neuroepithelial cells was significantly increased in the DM-WT group, and was significantly decreased in the DM-Tg group. Conclusions/interpretation These results indicate that oxidative stress is involved in diabetic embryopathy, and that the antioxidative protein TRX at least partially prevents diabetic embryopathy via suppression of apoptosis.

show abstract

Section: Introductionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

et al. 2010

View full text Add to dashboard Cite

show abstract

“…In normal mice, blood glucose increases at gd4.5 (32). All pregnant NOD mice (normoglycemic, n ϭ 5; pre-diabetic, n ϭ 7; diabetic, n ϭ 7) displayed significant increases in blood glucose from their individual baselines (three prior measurements; Fig.…”

Section: Pregnancy Accelerates Progression To Overt Diabetesmentioning

confidence: 90%

Aberrant Endometrial Features of Pregnancy in Diabetic NOD Mice

et al. 2007

View full text Add to dashboard Cite

OBJECTIVE-Pregnant diabetic women are at a 4 -12 times higher risk for preeclampsia, an urgent acute-onset complication of mid-to late gestation, than normal pregnant women. Hallmarks of preeclampsia are hypertension, proteinuria, and incomplete modification of endometrial spiral arteries. Transient proangiogenic lymphocytes called uterine natural killer (uNK) cells are implicated in human and rodent spiral artery modification. We studied mid-to late gestations in spontaneously type 1 diabetic NOD mice to investigate whether diabetes alters uNK cell homing and/or function.RESEARCH DESIGN AND METHODS-Normoglycemic, prediabetic, and diabetic NOD mice and controls were mated. Lymphocytes and endometrial endothelium and decidua were studied histologically and in functional assays.RESULTS-Conception accelerated progression to overt diabetes in NOD females who had limited spiral artery development, heavier placentas, and lighter fetuses displaying numerous birth defects compared with controls. UNK cell numbers were reduced in the decidua basalis of diabetic females, whereas interferon-␥ production was elevated. In diabetic NOD mice, decidual expression of the mucosal vascular addressin cell adhesion molecule (MAdCAM)-1 was aberrant in position, whereas vascular cell adhesion molecule (VCAM)-1 expression was reduced. Assays of lymphocyte adhesion to tissue sections under shear forces indicated that diabetes compromises the potential homing functions of both endometrial endothelium and peripheral NK cells.CONCLUSIONS-In diabetes, gestational endometrium has immune and vascular defects that likely contribute to murine fetal loss and birth defects. Analogous problems and preeclampsia in diabetic women may involve similar mechanisms. Diabetes

show abstract

“…It has been widely shown that maternal diabetes induces hypoxia, oxidative stress and other metabolic disturbances in the embryo [31] and these changes alter several signalling pathways and molecules which have been proposed to be the major causative factors for the diabetes-induced malformations leading to embryopathy. For example, the oxidative stress caused by hyperglycemia has been shown to disrupt the expression of genes such as Pax3 that is involved in neural tube formation which explains in part that hyperglycemia-induced oxidative stress alters gene expression leading to NTD [32] . Hyperglycemia-induced birth defects are attributed to the excessive production of reactive oxygen species (ROS) which has been shown to cause oxidative stress and subsequently increase the risk for fetal malformations [33,34] .…”

Section: Characterisation Of Metabolic Pathways In Ntdsmentioning

confidence: 99%

Frontiers in research on maternal diabetes-induced neural tube defects: Past, present and future

Sudhaharan

Bay²,

Tay³

et al. 2012

WJD

View full text Add to dashboard Cite

Diabetes mellitus rightly regarded as a silent-epidemic is continually on the rise and estimated to have a global prevalence of 6.4 % as of 2010. Diabetes during pregnancy is a well known risk factor for congenital anomalies in various organ systems that contribute to neonatal mortality, including cardiovascular, gastrointestinal, genitourinary and neurological systems, among which the neural tube defects are frequently reported. Over the last two to three decades, several groups around the world have focussed on identifying the molecular cues and cellular changes resulting in altered gene expression and the morphological defects and in diabetic pregnancy. In recent years, the focus has gradually shifted to looking at pre-programmed changes and activation of epigenetic mechanisms that cause altered gene expression. While several theories such as oxidative stress, hypoxia, and apoptosis triggered due to hyperglycemic conditions have been proposed and proven for being the cause for these defects, the exact mechanism or the link between how high glucose can alter gene expression/transcriptome and activate epigenetic mechanisms is largely unknown. Although preconceptual control of diabetes, (i.e., managing glucose levels during pregnancy), and in utero therapies has been proposed as an effective solution for managing diabetes during pregnancy, the impact that a fluctuating glycemic index can have on foetal development has not been evaluated in detail. A tight glycemic control started before pregnancy has shown to reduce the incidence of congenital abnormalities in diabetic mothers. On the other hand, a tight glycemic control after organogenesis and embryogenesis have begun may prove insufficient to prevent or reverse the onset of congenital defects. The importance of determining the extent to which glycemic levels in diabetic mothers should be regulated is critical as foetal hypoglycemia has also been shown to be teratogenic. Finally, the major question remaining is if this whole issue is negligible and not worthy of investigation as the efficient management of diabetes during pregnancy is well in place in many countries.

show abstract

Advances in Understanding the Molecular Causes of Diabetes-Induced Birth Defects

Cited by 91 publications

References 80 publications

Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

Aberrant Endometrial Features of Pregnancy in Diabetic NOD Mice

Frontiers in research on maternal diabetes-induced neural tube defects: Past, present and future

Contact Info

Product

Resources

About