The pathogenesis of congenital malformations in diabetic pregnancy

Eriksson, Ulf J.

doi:10.1002/dmr.5610110106

Cited by 45 publications

(27 citation statements)

References 192 publications

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“…Alternatively, and perhaps more likely, if the skewing of the sex ratio of live fetuses toward the male (Table 3) ratio of either normal or malformed fetuses. Likewise, epidemiological studies that address diabetes-induced birth defects do not mention sex of either normal or malformed infants (1,9). The finding that the fetal sex ratio is altered in this murine model of diabetic embryopathy bears further investigation as to causation and whether this phenomenon also occurs in humans.…”

Section: Discussionmentioning

confidence: 93%

“…Thus, Pax3 haploinsufficiency in this murine model of diabetic embryopathy is associated with caudal but not cranial NTDs. Diabetes 50:1193-1199, 2001 E mbryopathy resulting from maternal type 1 or type 2 diabetes is a well-established phenomenon, with the risk of a birth defect in a diabetic pregnancy being at least two and as much as six times higher than normal (1)(2)(3). Maternal diabetes has the potential to adversely affect the development of multiple organ systems, resulting in a wide range of congenital malformations.…”

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confidence: 99%

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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: 93%

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confidence: 99%

Diabetic Embryopathy in C57BL/6J Mice

et al. 2001

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“…The first is an increased supply of nutrients to the fetus in obese women. In animal models, an excess of several types of fuels (glucose, ketone bodies, NEFA, amino acids) was embryotoxic [25], probably acting through increased oxidative stress [26]. A second possible mechanism is hyperinsulinaemia itself.…”

Section: Resultsmentioning

confidence: 99%

In human gestational diabetes mellitus congenital malformations are related to pre-pregnancy body mass index and to severity of diabetes

et al. 2004

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Aims/hypothesis. This study analysed the relationship between congenital malformations (CM) and severity of gestational diabetes mellitus. Methods. A cohort of 2060 infants of mothers with gestational diabetes was studied. Universal screening and 3 rd Workshop-Conference criteria were used to diagnose gestational diabetes. The severity of diabetes was assessed on the basis of previous hyperglycaemia, blood glucose values in diagnostic OGTT, area under the glucose curve, gestational age and HbA 1 c at diagnosis, insulin requirements during pregnancy, and OGTT after delivery. Potentially confounding variables (age, pre-pregnancy BMI, smoking) were considered. The relationship of potential predictors with CM was analysed with several multivariate logistic regression analyses.Results. The rate of CM was 6% for minor and 3.8% for major malformations (1.4% heart, 0.8% renal/urinary, 0.7% skeletal, 0.3% hypospadias, 0.2% central nervous system, 0.2% cleft lip/palate, 0.1% digestive tract, 0.3% other). In the final models, forward logistic regression analysis identified pre-pregnancy BMI as the predictor of CM (area under receiver operating characteristic curve 0.616); in the backward analysis additional predictors were 1-h blood glucose in diagnostic OGTT and gestational age at diagnosis (area under receiver operating characteristic curve 0.646). Both BMI and severity of gestational diabetes were predictors of heart and minor CM, whereas BMI predicted renal/urinary CM and severity of diabetes predicted skeletal CM. Conclusions/interpretation. In these infants of mothers with gestational diabetes, severity of diabetes and pre-pregnancy BMI were predictors of CM, in accordance with the well-documented pathogenic role of BMI (in the general population) and hyperglycaemia (in diabetic pregnancy). BMI was the main predictor of more prevalent CM. [Diabetologia (2004) 47:509-514]

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“…Congenital malformations occur during early organogenesis and are responsible for the majority of the neonatal mortality and morbidity in pregnancies complicated by diabetes. That a strategy for glycemic control by insulin treatment during major organ development may significantly reduce embryonic malformations [40] , principally links hyperglycemia as playing an important role in diabetic teratogenesis. This is more so given that maternal glucose passes freely through the placenta and therefore the fetal serum glucose concentrations reflect the level present in the mother [41] .…”

Section: Diabetic Embryopathymentioning

confidence: 99%

Free Radicals, Antioxidants and Diabetes: Embryopathy, Retinopathy, Neuropathy, Nephropathy and Cardiovascular Complications

et al. 2006

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The metabolic disturbances in the insulin-dependent diabetes mellitus or type 1 and noninsulin-dependent diabetes mellitus or type 2 are associated with a number of complications including cardiovascular diseases, nephropathy, neuropathy, retinopathy leading to blindness and embryopathy or congenital malformations. Maternal diabetes is associated with a high incidence of congenital malformations and fetal abortions. Heart and kidney anomalies, along with central nervous system defects are frequent manifestations of a maternal diabetic environment. Glycation products from excess glucose can chemically modify DNA causing mutations and complex DNA rearrangements. Therefore, DNA damage in fetal tissues as a result of maternal diabetes may reflect a level of genomic injury sufficient to affect embryonic development. The formation of advanced glycation end products can accelerate vascular occlusion by quenching the vasodilating agent nitric oxide. Interaction with high-affinity receptors located on monocytes and macrophages can enhance the production of free radicals and reactive oxygen/nitrogen species, the secretion of tumor necrosis factor-α, interleukin-1 and insulin-like growth factor 1 which can proliferate endothelial, mesangial and smooth muscle cells and hence contribute significantly to the pathogenesis of cardiovascular complications. Retinopathy is characterized by increased vascular permeability, by vascular closure, together with the growth of new blood vessels on the retina and posterior surface of the vitreous. Reactive oxygen species are involved in decreased retinal blood flow, increased vascular permeability and disruption of blood-retinal barrier. The involvement of oxidative stress in the pathology of diabetes from its associated cardiovascular dysfunctions, nephropathy, neuropathy, retinopathy (leading to blindness) and embryopathy or congenital malformations, suggests that potential management of diabetes could benefit from use of dietary biofactors in medicinal and food plants. There is therefore a requirement for research to focus on the molecular mechanisms of action of extracts and/or the biofactors flavonoids, proanthocyanidins, alkaloids, etc. derived from these plants.

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The pathogenesis of congenital malformations in diabetic pregnancy

Cited by 45 publications

References 192 publications

Diabetic Embryopathy in C57BL/6J Mice

Diabetic Embryopathy in C57BL/6J Mice

In human gestational diabetes mellitus congenital malformations are related to pre-pregnancy body mass index and to severity of diabetes

Free Radicals, Antioxidants and Diabetes: Embryopathy, Retinopathy, Neuropathy, Nephropathy and Cardiovascular Complications

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