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    PAPPA-mediated adipose tissue remodeling mitigates insulin resistance and protects against gestational diabetes in mice and humans. Science translational medicine Pregnancy is a physiological state of continuous adaptation to changing maternal and fetal nutritional needs, including a reduction of maternal insulin sensitivity allowing for appropriately enhanced glucose availability to the fetus. However, excessive insulin resistance in conjunction with insufficient insulin secretion results in gestational diabetes mellitus (GDM), greatly increasing the risk for pregnancy complications and predisposing both mothers and offspring to future metabolic disease. Here, we report a signaling pathway connecting pregnancy-associated plasma protein A (PAPPA) with adipose tissue expansion in pregnancy. Adipose tissue plays a central role in the regulation of insulin sensitivity, and we show that, in both mice and humans, pregnancy caused remodeling of adipose tissue evidenced by altered adipocyte size, vascularization, and in vitro expansion capacity. PAPPA is known to be a metalloprotease secreted by human placenta that modulates insulin-like growth factor (IGF) bioavailability through prolteolysis of IGF binding proteins (IGFBPs) 2, 4, and 5. We demonstrate that recombinant PAPPA can stimulate ex vivo human adipose tissue expansion in an IGFBP-5- and IGF-1-dependent manner. Moreover, mice lacking PAPPA displayed impaired adipose tissue remodeling, pregnancy-induced insulin resistance, and hepatic steatosis, recapitulating multiple aspects of human GDM. In a cohort of 6361 pregnant women, concentrations of circulating PAPPA are inversely correlated with glycemia and odds of developing GDM. These data identify PAPPA and the IGF signaling pathway as necessary for the regulation of maternal adipose tissue physiology and systemic glucose homeostasis, with consequences for long-term metabolic risk and potential for therapeutic use. 10.1126/scitranslmed.aay4145
    Downregulated ABHD5 Aggravates Insulin Resistance of Trophoblast Cells During Gestational Diabetes Mellitus. Peng Hai-Yan,Li Hua-Ping,Li Ming-Qing Reproductive sciences (Thousand Oaks, Calif.) Lipid metabolism-associated molecule abhydrolase domain containing 5 (ABHD5) has been reported to have a role in insulin-mediated glucose uptake, the deregulation of it is associated with gestational diabetes mellitus (GDM). However, whether ABHD5 participates in glucose metabolism disorders in GDM patients has remained elusive. The present study aimed to clarify the role of ABHD5 in regulating insulin signaling in placentae during GDM. Reverse transcription-quantitative polymerase chain reaction (qRT-PCR) analysis was used for detecting the levels of ABHD5 and AMP kinase (AMPK), the insulin signaling molecules insulin receptor (INSR), INSR substrate (IRS1, IRS2), phosphoinositide 3-kinase (PI3K) and AKT, as well as the glucose transporter type 4 (GLUT-4) in placentae and the trophoblast cell line HTR-8/SVneo, while the protein level of ABHD5 was determined by western blotting. Pearson correlation analysis was performed to assess the correlation between the levels of ABHD5 and AMPK in placentae. In addition, ABHD5 overexpression in HTR-8/SVneo cells was achieved using plasmid vectors. The results indicated that the expression of ABHD5 and AMPK was dampened in placental tissues of females with GDM, and the levels of ABHD5 were positively correlated with AMPK. High-glucose (HG) treatment suppressed the expression of ABHD5, AMPK, GLUT-4, INSR, IRS, PI3K, and AKT in HTR-8/SVneo cells, and the overexpression of ABHD5 caused an elevation of the expression of these genes under normal and HG conditions in vitro. In conclusion, HG conditions induce insulin resistance of HTR-8/SVneo cells through downregulating ABHD5, which may account for impaired insulin signaling of placental tissues in GDM women. 10.1007/s43032-019-00010-x
    Downregulation of microRNA-873 attenuates insulin resistance and myocardial injury in rats with gestational diabetes mellitus by upregulating IGFBP2. Han Na,Fang Hai-Yan,Jiang Jie-Xuan,Xu Qian American journal of physiology. Endocrinology and metabolism Gestational diabetes mellitus (GDM) is a metabolic disorder characterized by insulin resistance, and patients with GDM have a higher risk of cardiovascular disease. Multiple microRNAs (miRNAs) are reported to be involved in the regulation of myocardial injury. Moreover, miR-873 was predicted to target insulin-like growth factor binding protein 2 (IGFBP2) through bioinformatic analysis, which was further confirmed using a luciferase assay. Thus, our objective was to assess whether microRNA-873 (miR-873) affects insulin resistance and myocardial injury in an established GDM rat model. The GDM rats were treated with miR-875 mimic or inhibitor or IGFBP2 siRNA. The effects of miR-875 and IGFBP2 on the cardiac function, insulin resistance, and myocardial injury were evaluated by hemodynamic measurements, determination of biochemical indices of myocardium and serum, and insulin homeostatic model assessment. The results indicated that downregulation of miR-873 upregulated the expression of IGFBP2 and promoted the activation of phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis. With downregulation of miR-873 in GDM rats, the cardiac function was improved and the myocardial apoptosis was inhibited, coupled with elevated activity of superoxide dismutase, carbon monoxide synthase, and the nitric oxide content. In addition, the inhibition of miR-873 in GDM rats modulated the insulin resistance and reduced myocardial apoptosis. Overall, the data showed that inhibition of miR-873 by targeting may regulate the insulin resistance and curtail myocardial injury in GDM rats through activating the PI3K/AKT/mTOR axis, thus providing a potential means of impeding the progression of GDM. 10.1152/ajpendo.00555.2018
    Cinnamaldehyde mitigates placental vascular dysfunction of gestational diabetes and protects from the associated fetal hypoxia by modulating placental angiogenesis, metabolic activity and oxidative stress. Hosni Ahmed,El-Twab Sanaa Abd,Abdul-Hamid Manal,Prinsen Els,AbdElgawad Hamada,Abdel-Moneim Adel,Beemster Gerrit T S Pharmacological research Gestational diabetes mellitus (GDM) is a major pregnancy-related disorder with an increasing prevalence worldwide. GDM is associated with altered placental vascular functions and has severe consequences for fetal growth. There is no commonly accepted medication for GDM due to safety considerations. Actions of the currently limited therapeutic options focus exclusively on lowering the blood glucose level without paying attention to the altered placental vascular reactivity and remodelling. We used the fat-sucrose diet/streptozotocin (FSD/STZ) rat model of GDM to explore the efficacy of cinnamaldehyde (Ci; 20 mg/kg/day), a promising antidiabetic agent for GDM, and glyburide/metformin-HCl (Gly/Met; 0.6 + 100 mg/kg/day), as a reference drug for treatment of GDM, on the placenta structure and function at term pregnancy after their oral intake one week before mating onward. Through genome-wide transcriptome, biochemical, metabolome, metal analysis and histopathology we obtained an integrated understanding of their effects. GDM resulted in maternal and fetal hyperglycemia, fetal hyperinsulinemia and placental dysfunction with subsequent fetal anemia, hepatic iron deficiency and high serum erythropoietin level, reflecting fetal hypoxia. Differentially-regulated genes were overrepresented for pathways of angiogenesis, metabolic transporters and oxidative stress. Despite Ci and Gly/Met effectively alleviated the maternal and fetal glycemia, only Ci offered substantial protection from GDM-associated placental vasculopathy and prevented the fetal hypoxia. This was explained by Ci's impact on the molecular regulation of placental angiogenesis, metabolic activity and redox signaling. In conclusion, Ci provides a dual impact for the treatment of GDM at both maternal and fetal levels through its antidiabetic effect and the direct placental vasoprotective action. Lack of Gly/Met effectiveness to restore it's impaired functionality demonstrates the vital role of the placenta in developing efficient medications for GDM. 10.1016/j.phrs.2021.105426