scholarly journals Maternal Cognitive Impairment Associated with Gestational Diabetes Mellitus—A Review of Potential Contributing Mechanisms

2018 ◽  
Vol 19 (12) ◽  
pp. 3894 ◽  
Author(s):  
Cini John ◽  
Nur Mohamed Yusof ◽  
Siti Abdul Aziz ◽  
Fazlin Mohd Fauzi
Keyword(s):  
Diabetes Mellitus ◽  
Cognitive Impairment ◽  
Cognitive Function ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Insulin Signaling Pathway ◽  
Serine Phosphorylation ◽  
Τ Protein

Gestational diabetes mellitus (GDM) carries many risks, where high blood pressure, preeclampsia and future type II diabetes are widely acknowledged, but less focus has been placed on its effect on cognitive function. Although the multifactorial pathogenesis of maternal cognitive impairment is not completely understood, it shares several features with type 2 diabetes mellitus (T2DM). In this review, we discuss some key pathophysiologies of GDM that may lead to cognitive impairment, specifically hyperglycemia, insulin resistance, oxidative stress, and neuroinflammation. We explain how these incidents: (i) impair the insulin-signaling pathway and/or (ii) lead to cognitive impairment through hyperphosphorylation of τ protein, overexpression of amyloid-β and/or activation of microglia. The aforementioned pathologies impair the insulin-signaling pathway primarily through serine phosphorylation of insulin receptor substances (IRS). This then leads to the inactivation of the phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) signaling cascade, which is responsible for maintaining brain homeostasis and normal cognitive functioning. PI3K/AKT is crucial in maintaining normal cognitive function through the inactivation of glycogen synthase kinase 3β (GSκ3β), which hyperphosphorylates τ protein and releases pro-inflammatory cytokines that are neurotoxic. Several biomarkers were also highlighted as potential biomarkers of GDM-related cognitive impairment such as AGEs, serine-phosphorylated IRS-1 and inflammatory markers such as tumor necrosis factor α (TNF-α), high-sensitivity C-reactive protein (hs-CRP), leptin, interleukin 1β (IL-1β), and IL-6. Although GDM is a transient disease, its complications may be long-term, and hence increased mechanistic knowledge of the molecular changes contributing to cognitive impairment may provide important clues for interventional strategies.

scholarly journals Defective insulin signaling in placenta from pregnancies complicated by gestational diabetes mellitus

2009 ◽  
Vol 160 (4) ◽  
pp. 567-578 ◽  
Author(s):  
Michelle Colomiere ◽  
Michael Permezel ◽  
Clyde Riley ◽  
Gernot Desoye ◽  
Martha Lappas
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
Placental Tissue ◽  
Insulin Signaling Pathway ◽  
Obese Patients ◽  
Obese Women ◽  
Normal Controls

ObjectiveStudies in adipose tissue and skeletal muscle suggest that impaired insulin action is due to defects in the insulin signaling pathway and may play a role in the pathophysiology of insulin resistance associated with gestational diabetes mellitus (GDM) and obesity. The present study tested the hypothesis that endogenous expression levels in the human term placenta of insulin signaling components are altered in placental tissue from GDM women in comparison with normal controls and maternal obesity.Design and methodsPlacental tissue was collected from normal, diet-controlled GDM, and insulin-controlled GDM in both non-obese and obese women (n=6–7 per group). Western blotting and quantitative RT-PCR was performed to determine the level of expression in the insulin signaling pathway.ResultsThere was a significant increase in insulin receptor (IR) substrate (IRS)-1 protein expression with a concurrent decrease in IRS-2 protein expression in non-obese women with insulin-controlled GDM compared with diet-controlled GDM and normal controls. Furthermore, a decrease in both protein and mRNA expression of phosphatidyl-inositol-3-kinase (PI3-K) p85α and glucose transporter (GLUT)-4 was observed in non-obese and obese women with insulin controlled GDM compared with normal controls. When comparing non-obese to obese patients, significant decreases in mRNA expression of IR-β, PI3K p85α and GLUT-4 was found in obese patients.ConclusionOur results suggest that post receptor defects are present in the insulin signaling pathway in placenta of women with pregnancies complicated by diabetes and obesity. In addition, expression studies demonstrate post receptor alterations in insulin signaling possibly under selective maternal regulation and not fetal regulation.

scholarly journals Oleuropein alleviates gestational diabetes mellitus by activating AMPK signaling

2020 ◽  
Author(s):  
Zhiwei Zhang ◽  
Hui Zhao ◽  
Aixia Wang
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Body Weight ◽  
Blood Glucose ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Signaling Pathway ◽  
Hepatic Glycogen ◽  
Ampk Signaling ◽  
Tnf Α

Background: Gestational diabetes mellitus (GDM) has a high incidence rate among pregnant women. The objective of the study was to assess the effect of plant-derived oleuropein in attenuating inflammatory and oxidative stress of GDM. Methods: Oleuropein was administered to GDM mice at the doses of 5 or 10 mg/kg/day. Body weight, blood glucose, insulin and hepatic glycogen levels were recorded. To evaluate the effect of oleuropein in reducing oxidative stress, enzyme-linked immunosorbent assay (ELISA) was used to measure the hepatic oxidative stress markers. The inflammation levels of GDM mice were evaluated by measuring serum levels of IL-6 and TNF-α by ELISA, and mRNA levels of IL-1β, TNF-α and IL-6 by real-time PCR (RT-PCR). The AMP-activated protein kinase (AMPK) signaling pathway was assessed by Western blot. Gestational outcome was analyzed through comparing litter size and birth weight. Results: Oleuropein attenuated the elevated body weight of GDM mice, and efficiently reduced blood glucose, insulin and hepatic glycogen levels. Oxidative stress and inflammation were alleviated by oleuropein treatment. The AMPK signaling was activated by oleuropein in GDM mice. Gestational outcome was markedly improved by oleuropein treatment. Conclusions: Our study suggests that oleuropein is effective in alleviating symptoms of GDM and improving gestational outcome in the mouse model. This effect is achieved by attenuating oxidative stress and inflammation, which is mediated by the activation of the AMPK signaling pathway.

scholarly journals Cognitive Dysfunction of Pregnant Women with Gestational Diabetes Mellitus in Perinatal Period

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Siriguleng Sana ◽  
Xijin Deng ◽  
Lei Guo ◽  
Xunhong Wang ◽  
Enyou Li
Keyword(s):  
Diabetes Mellitus ◽  
Blood Glucose ◽  
Cognitive Function ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Pregnant Women ◽  
Cognitive Dysfunction ◽  
Statistical Significance ◽  
Venous Blood ◽  
Perinatal Period

Purpose. To explore whether pregnant women with gestational diabetes mellitus (GDM) had cognitive impairment and assess cognitive function in normal pregnant women. Methods. A total of 75 consecutive women diagnosed with GDM (GDM group), 70 normal pregnant women (NP group) without diabetes and matched for age, and 51 female volunteers (CG group) with the similar age level, normal blood glucose, and nonpregnancy were included in the study. For the assessment of cognitive functions, Montreal Cognitive Assessment (MoCA) was performed. Venous blood samples were collected to measure blood glucose, glycated hemoglobin (HbA1c), methylglyoxal (MGO), beta amyloid (Aβ), and tau protein. Results. The score of MoCA of GDM was lowest, and the score of the NP group was lower than volunteers ( P < 0.05 ). The incidence of cognitive dysfunction increased significantly in the GDM group with statistical significance ( P < 0.05 ). The levels of tau and MGO in the GDM group were significantly less than those in the NP and CG groups, and Aβ in the GDM group was significantly more than that in the NP and CG groups ( P < 0.05 ), but the differences between NP and CG groups were not statistically significant ( P < 0.05 ). Conclusion. The pregnant women with GDM showed a significant decline in cognitive function, and the normal pregnant women also showed a decline in cognitive function which is very light.

scholarly journals Upregulation of IL-15 in the placenta alters trophoblasts behavior contributing to gestational diabetes mellitus

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jiaqi Li ◽  
Yuan Li ◽  
Xuan Zhou ◽  
Lijie Wei ◽  
Jingyi Zhang ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Signaling Pathway ◽  
Blood Glucose Concentration ◽  
Biological Behavior ◽  
Oral Glucose ◽  
Obesity And Diabetes ◽  
Stat Signaling

Abstract Background Interleukin-15 (IL-15), a member of the ‘four α-helix bundle’ cytokine family, has been associated with many inflammatory and metabolic diseases. Abnormal expression of IL-15 has been linked to the occurrence and development of obesity and diabetes. However, there is a paucity of research on the involvement of IL-15 in Gestational Diabetes Mellitus (GDM). This study aims at investigating the role of IL-15 in the pathogenesis of GDM. Results IL-15 was consistently expressed in the placenta throughout pregnancy and dynamically changed with pregnancy progress. Trophoblasts have been identified as the major source of IL-15 in the placenta. Expression of IL-15 was significantly increased in the placenta of GDM and in the trophoblasts cultured with high glucose (HG). In our study, expression of IL-15 in the placenta was positively correlated with blood glucose concentration of 75 g Oral Glucose Tolerance Test (OGTT), and was inversely correlated with weight of newborns. Further investigations in vitro showed that exogenous addition of IL-15 promoted trophoblasts proliferation, improved invasion and tube formation ability by activating the JAK/STAT signaling pathway, which be blocked by JAK inhibitors. Conclusion Our results demonstrated that IL-15 expression in the placenta was dynamically changing during pregnancy, and it was upregulated in the placenta of GDM patients. Furthermore, IL-15 altered the biological behavior of trophoblasts through JAK/STAT signaling pathway in vitro, and may contributed to the placental pathology of GDM. Our findings provide a new direction for studying the pathophysiological changes of placenta in GDM.

scholarly journals Hypochlorous acid via peroxynitrite activates protein kinase Cθ and insulin resistance in adipocytes

2014 ◽  
Vol 54 (1) ◽  
pp. 25-37 ◽  
Author(s):  
Jun Zhou ◽  
Qilong Wang ◽  
Ye Ding ◽  
Ming-Hui Zou
Keyword(s):  
Insulin Resistance ◽  
Signaling Pathway ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Hypochlorous Acid ◽  
Insulin Signaling Pathway ◽  
Serine Phosphorylation ◽  
Impaired Insulin ◽  
Genetic Deletion

We recently reported that genetic deletion of myeloperoxidase (MPO) alleviates obesity-related insulin resistance in mice in vivo. How MPO impairs insulin sensitivity in adipocytes is poorly characterized. As hypochlorous acid (HOCl) is a principal oxidant product generated by MPO, we evaluated the effects of HOCl on insulin signaling in adipocytes differentiated from 3T3-L1 cells. Exposure of 3T3-L1 adipocytes to exogenous HOCl (200 μmol/l) attenuated insulin-stimulated 2-deoxyglucose uptake, GLUT4 translocation, and insulin signals, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and phosphorylation of Akt. Furthermore, treatment with HOCl induced phosphorylation of IRS1 at serine 307, inhibitor κB kinase (IKK), c-Jun NH2-terminal kinase (JNK), and phosphorylation of PKCθ (PKCθ). In addition, genetic and pharmacological inhibition of IKK and JNK abolished serine phosphorylation of IRS1 and impairment of insulin signaling by HOCl. Furthermore, knockdown of PKCθ using siRNA transfection suppressed phosphorylation of IKK and JNK and consequently attenuated the HOCl-impaired insulin signaling pathway. Moreover, activation of PKCθ by peroxynitrite was accompanied by increased phosphorylation of IKK, JNK, and IRS1-serine 307. In contrast, ONOO− inhibitors abolished HOCl-induced phosphorylation of PKCθ, IKK, JNK, and IRS1-serine 307, as well as insulin resistance. Finally, high-fat diet (HFD)-induced insulin resistance was associated with enhanced phosphorylation of PKCθ, IKK, JNK, and IRS1 at serine 307 in white adipose tissues from WT mice, all of which were not found in Mpo knockout mice fed HFDs. We conclude that HOCl impairs insulin signaling pathway by increasing ONOO− mediated phosphorylation of PKCθ, resulting in phosphorylation of IKK/JNK and consequent serine phosphorylation of IRS1 in adipocytes.

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