Diabetes mellitus and birth defects

Correa, Adolfo; Gilboa, Suzanne M.; Besser, Lilah M.; Botto, Lorenzo D.; Moore, Cynthia A.; Hobbs, Charlotte A.; Cleves, Mario A.; Riehle‐Colarusso, Tiffany; Waller, D. Kim; Reece, E. Albert

doi:10.1016/j.ajog.2008.06.028

Cited by 546 publications

(477 citation statements)

References 37 publications

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“…We also wanted to induce autophagy in a way that would have the lowest probability of toxic effects. For that reason, we decided to use trehalose, a nontoxic disaccharide that has been shown to induce autophagy and to have neuroprotective effects in animal models of Huntington disease, Alzheimer's disease, Parkinson's disease, ALS, and maternal diabetes-associated neural tube defects in the embryo (13,(15)(16)(17)(18)(19)(20). In addition to the positive effects of trehalose in neurodegenerative diseases, there is also evidence that trehalose may have a beneficial effect on impaired endothelial cells in ageing arteries, a risk factor for cardiovascular disease (49).…”

Section: Discussionmentioning

confidence: 99%

“…It is known that neural tube defects are greatly increased in the offspring of women with pregestational diabetes. In a mouse model of maternal diabetes that leads to autophagy impairment in neuroepithelial cells and neural tube defects in the embryo, administration of trehalose in the drinking water prevents these neural tube defects (19,20). Although most studies have examined trehalose in the context of inducing macroautophagy, there is some evidence that it can also induce CMA and counter the effects of the proteasome inhibitor epoxomicin, including elevated reactive oxygen species (ROS), cleaved caspase 3, increased levels of ubiquitinated proteins, and mitochondrial dysfunction and altered morphology (21,22).…”

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confidence: 99%

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Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types

Belzile

Sabalza

Craig

et al. 2016

J Virol

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Human cytomegalovirus (HCMV) is the major viral cause of birth defects and a serious problem in immunocompromised individuals and has been associated with atherosclerosis. Previous studies have shown that the induction of autophagy can inhibit the replication of several different types of DNA and RNA viruses. The goal of the work presented here was to determine whether constitutive activation of autophagy would also block replication of HCMV. Most prior studies have used agents that induce autophagy via inhibition of the mTOR pathway. However, since HCMV infection alters the sensitivity of mTOR kinase-containing complexes to inhibitors, we sought an alternative method of inducing autophagy. We chose to use trehalose, a nontoxic naturally occurring disaccharide that is found in plants, insects, microorganisms, and invertebrates but not in mammals and that induces autophagy by an mTOR-independent mechanism. Given the many different cell targets of HCMV, we proceeded to determine whether trehalose would inhibit HCMV infection in human fibroblasts, aortic artery endothelial cells, and neural cells derived from human embryonic stem cells. We found that in all of these cell types, trehalose induces autophagy and inhibits HCMV gene expression and production of cell-free virus. Treatment of HCMV-infected neural cells with trehalose also inhibited production of cell-associated virus and partially blocked the reduction in neurite growth and cytomegaly. These results suggest that activation of autophagy by the natural sugar trehalose or other safe mTOR-independent agents might provide a novel therapeutic approach for treating HCMV disease. IMPORTANCEHCMV infects multiple cell types in vivo, establishes lifelong persistence in the host, and can cause serious health problems for fetuses and immunocompromised individuals. HCMV, like all other persistent pathogens, has to finely tune its interplay with the host cellular machinery to replicate efficiently and evade detection by the immune system. In this study, we investigated whether modulation of autophagy, a host pathway necessary for the recycling of nutrients and removal of protein aggregates, misfolded proteins, and pathogens, could be used to target HCMV. We found that autophagy could be significantly increased by treatment with the nontoxic, natural disaccharide trehalose. Importantly, trehalose had a profound inhibitory effect on viral gene expression and strongly impaired viral spread. These data constitute a proof-of-concept for the use of natural products targeting host pathways rather than the virus itself, thus reducing the risk of the development of resistance to treatment. H uman cytomegalovirus (HCMV) infects multiple cell types, including endothelial, smooth muscle, epithelial, and fibroblast cells, monocytes/macrophages, bone marrow progenitor cells, and cells of the neural lineage, and establishes lifelong persistence in the host (for a review, see reference 1). Seroprevalence is high in the general population, and in most healthy individuals, the in...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types

Belzile

Sabalza

Craig

et al. 2016

J Virol

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“…Such defects are not necessarily caused by genetic alterations, with epidemiological studies having revealed that various modifiable factors increase the risk of specific types of CHD (1,3). Pregestational diabetes mellitus (DM), including both type 1 and type 2 DM, is one such modifiable factor (1,3,4).…”

mentioning

confidence: 99%

“…Pregestational DM gives rise to CHDs associated with heterotaxia in humans (1,4,15,16). Heterotaxia also occurs in offspring of diabetic female nonobese diabetic mice, a model of type 1 DM.…”

mentioning

confidence: 99%

Hyperglycemia impairs left–right axis formation and thereby disturbs heart morphogenesis in mouse embryos

Hachisuga

Oki

Kitajima

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Congenital heart defects with heterotaxia are associated with pregestational diabetes mellitus. To provide insight into the mechanisms underlying such diabetes-related heart defects, we examined the effects of high-glucose concentrations on formation of the left-right axis in mouse embryos. Expression of Pitx2, which plays a key role in left-right asymmetric morphogenesis and cardiac development, was lost in the left lateral plate mesoderm of embryos of diabetic dams. Embryos exposed to high-glucose concentrations in culture also failed to express Nodal and Pitx2 in the left lateral plate mesoderm. The distribution of phosphorylated Smad2 revealed that Nodal activity in the node was attenuated, accounting for the failure of left-right axis formation. Consistent with this notion, Notch signal-dependent expression of Nodal-related genes in the node was also down-regulated in association with a reduced level of Notch signaling, suggesting that high-glucose concentrations impede Notch signaling and thereby hinder establishment of the left-right axis required for heart morphogenesis.diabetes | congenital heart defects | heterotaxia | left-right axis

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“…A large case control study found that GDM was linked to a limited group of birth defects (when compared with pre-existing diabetes) and that this association was generally limited to women with a high body mass index (BMI) > 25 kg/m 2 [28].…”

Section: Introductionmentioning

confidence: 99%

Prediction of Gestational Diabetes Mellitus in Early Pregnancy: Is Abdominal Skin Fold Thickness 20 mm or More an Independent Risk Predictor?

Oriji¹,

Ojule²,

Fumudoh³

2017

JBM

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Background: Gestational Diabetes Mellitus (GDM) is associated with several maternal and perinatal complications. Early detection and treatment can improve pregnancy outcomes. Objectives: To determine the prevalence, risk factors and predictors of GDM in early pregnancy at the University of Port Harcourt Teaching Hospital, (UPTH), Port Harcourt Nigeria. Methods: A cohort of 235 mothers who registered for antenatal care between 15 -18 weeks of gestation at UPTH was prospectively studied. Their socio-demographic data, examination findings, anthropometric measurements, fasting blood sugar at booking and OGTT results at 28 weeks gestation were collated and entered into PC with SPSS for windows version 21.0 which was also used for the analysis. Variables were expressed as absolute numbers, percentages or means with standard deviations and significant differences determined using chi square test or the student "t" test as appropriate. The level of significance was set at P < 0.05. Results: Of the 235 participants, 35 (14.9%) developed GDM.Women who had GDM were significantly older (P = 0.001), had higher weight (t = 2.95, P = 0.01), BMI (t = 2.29, P = 0.02), abdominal skin fold thickness (t = 4.15, P = 0.001), blood pressure (t = 3.38, P = 0.001) compared to women who did not. Previous history of GDM was significantly different between two groups as χ 2 = 93.56 and P = 0.001. Abdominal skin fold thickness and prior GDM history were found to be independent predictors of GDM on application of multiple logistic regression analysis. Conclusion: The prevalence of GDM in Port Harcourt is 14.9% and major risk factors are obesity, previous GDM history, advanced age and hypertension. Abdominal skin fold thickness ≥ 20 mm is an independent predictor. The risk of developing GDM can be

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Diabetes mellitus and birth defects

Abstract: PGDM was associated with a wide range of birth defects; GDM was associated with a limited group of birth defects.

Cited by 546 publications

References 37 publications

Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types

Trehalose, an mTOR-Independent Inducer of Autophagy, Inhibits Human Cytomegalovirus Infection in Multiple Cell Types

Hyperglycemia impairs left–right axis formation and thereby disturbs heart morphogenesis in mouse embryos

Prediction of Gestational Diabetes Mellitus in Early Pregnancy: Is Abdominal Skin Fold Thickness 20 mm or More an Independent Risk Predictor?

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