Akt/mTOR Role in Human Foetoplacental Vascular Insulin Resistance in Diseases of Pregnancy

Insulin resistance is characteristic of pregnancies where the mother shows metabolic alterations, such as preeclampsia (PE) and gestational diabetes mellitus (GDM), or abnormal maternal conditions such as pregestational maternal obesity (PGMO). Insulin signalling includes activation of insulin receptor substrates 1 and 2 (IRS1/2) as well as Src homology 2 domain-containing transforming protein 1, leading to activation of 44 and 42 kDa mitogen-activated protein kinases and protein kinase B/Akt (Akt) signalling cascades in the human foetoplacental vasculature. PE, GDM, and PGMO are abnormal conditions coursing with reduced insulin signalling, but the possibility of the involvement of similar cell signalling mechanisms is not addressed. This review aimed to determine whether reduced insulin signalling in PE, GDM, and PGMO shares a common mechanism in the human foetoplacental vasculature. Insulin resistance in these pathological conditions results from reduced Akt activation mainly due to inhibition of IRS1/2, likely due to the increased activity of the mammalian target of rapamycin (mTOR) resulting from lower activity of adenosine monophosphate kinase. Thus, a defective signalling via Akt/mTOR in response to insulin is a central and common mechanism of insulin resistance in these diseases of pregnancy. In this review, we summarise the cell signalling mechanisms behind the insulin resistance state in PE, GDM, and PGMO focused in the Akt/mTOR signalling pathway in the human foetoplacental endothelium.Unión Europea Framework Grant Agreement no. 295185–EULAMDIM

Endoplasmic reticulum stress and development of insulin resistance in adipose, skeletal, liver, and foetoplacental tissue in diabesity

Diabesity is an abnormal metabolic condition shown by patients with obesity that develop type 2 diabetes mellitus. Patients with diabesity present with insulin resistance, reduced vascular response to insulin, and vascular endothelial dysfunction. Along with the several well-described mechanisms of insulin resistance, a state of endoplasmic reticulum (ER) stress, where the primary human targets are the adipose tissue, liver, skeletal muscle, and the foetoplacental vasculature, is apparent. ER stress characterises by the activation of the unfolded protein response via three canonical ER stress sensors, i.e., the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6. Slightly different cell signalling mechanisms preferentially enable in diabesity in the ER stress-associated insulin resistance for adipose tissue (IRE1α/X-box binding protein 1 mRNA splicing/c-jun N-terminal kinase 1 activation), skeletal muscle (tribbles-like protein 3 (TRB3)/proinflammatory cytokines activation), and liver (PERK/activating transcription factor 4/TRB3 activation). There is no information in human subjects with diabesity in the foetoplacental vasculature. However, the available literature shows that pregnant women with pre-pregnancy obesity or overweight that develop gestational diabetes mellitus (GDM) and their newborn show insulin resistance. ER stress is recently reported to be triggered in endothelial cells from the human umbilical vein from mothers with pre-pregnancy obesity. However, whether a different metabolic alteration to obesity in pregnancy or GDM is present in women with pre-pregnancy obesity that develop GDM, is unknown. In this review, we summarised the findings on diabesity-associated mechanisms of insulin resistance with emphasis in the primary targets adipose, skeletal muscle, liver, and foetoplacental tissues. We also give evidence on the possibility of a new GDM-associated metabolic condition triggered in pregnancy by maternal obesity, i.e. gestational diabesity, leading to ER stress-associated insulin resistance in the human foetoplacental vasculature

Pre-pregnancy maternal obesity associates with endoplasmic reticulum stress in human umbilical vein endothelium

Obesity associates with the endoplasmic reticulum (ER) stress-induced endothelial dysfunction. Pregnant women with pre-pregnancy maternal obesity (PGMO) may transfer this potential risk to their offspring; however, whether ER stress occurs and associates with foetoplacental endothelial dysfunction in PGMO is unknown. We studied the l-arginine transport and nitric oxide (NO) synthesis in human umbilical vein endothelial cells (HUVECs) from women with PGMO or with a normal pre-pregnancy weight. We analysed the expression and activation of the ER stress sensors protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). PGMO associated with lower endothelial NO synthase activity due to increased Thr-inhibitor and decreased Ser-stimulator phosphorylation. However, higher expression and activity of the human cationic amino acid transporter 1 was found. PGMO caused activation of PERK and its downstream targets eukaryotic initiation factor 2 (eIF2α), C/EBP homologous protein 10 (CHOP), and tribbles-like protein 3 (TRB3). Increased IRE1α protein abundance (but not its phosphorylation or X-box binding protein 1-mRNA splicing) and increased c-Jun N-terminal kinase 1 phosphorylation was seen in PGMO. A preferential nuclear location of the activating transcription factor 6 (ATF6) was found in HUVECs from PGMO. All the changes seen in PGMO were blocked by TUDCA but unaltered by tunicamycin. Thus, PGMO may determine a state of ER stress via upregulation of the PERK-eIF2α-CHOP-TRB3 axis signalling in HUVECs. This phenomenon results in foetoplacental vascular endothelial dysfunction at birth

Molecular implications of adenosine in obesity

Adenosine has broad activities in organisms due to the existence of multiple receptors, the differential adenosine concentrations necessary to activate these receptors and the presence of proteins able to synthetize, degrade or transport this nucleoside. All adenosine receptors have been reported to be involved in glucose homeostasis, inflammation, adipogenesis, insulin resistance, and thermogenesis, indicating that adenosine could participate in the process of obesity. Since adenosine seems to be associated with several effects, it is plausible that adenosine participates in the initiation and development of obesity or may function to prevent it. Thus, the purpose of this review was to explore the involvement of adenosine in adipogenesis, insulin resistance and thermogenesis, with the aim of understanding how adenosine could be used to avoid, treat or improve the metabolic state of obesity. Treatment with specific agonists and/or antagonists of adenosine receptors could reverse the obesity state, since adenosine receptors normalizes several mechanisms involved in obesity, such as lipolysis, insulin sensitivity and thermogenesis. Furthermore, obesity is a preventable state, and the specific activation of adenosine receptors could aid in the prevention of obesity. Nevertheless, for the treatment of obesity and its consequences, more studies and therapeutic strategies in addition to adenosine are necessary

Extracellular histones activate autophagy and apoptosis via mTOR signaling in human endothelial cells

Circulating histones have been proposed as targets for therapy in sepsis and hyperinflammatory symptoms. However, the proposed strategies have failed in clinical trials. Although different mechanisms for histone-related cytotoxicity are being explored, those mediated by circulating histones are not fully understood. Extracellular histones induce endothelial cell death, thereby contributing to the pathogenesis of complex diseases such as sepsis and septic shock. Therefore, the comprehension of cellular responses triggered by histones is capital to design effective therapeutic strategies. Here we report how extracellular histones induce autophagy and apoptosis in a dose-dependent manner in cultured human endothelial cells. In addition, we describe how histones regulate these pathways via Sestrin2/AMPK/ULK1-mTOR and AKT/mTOR. Furthermore, we evaluate the effect of Toll-like receptors in mediating autophagy and apoptosis demonstrating how TLR inhibitors do not prevent apoptosis and/or autophagy induced by histones. Our results confirm that histones and autophagic pathways can be considered as novel targets to design therapeutic strategies in endothelial damage

Endothelial dysfunction in pregnancy metabolic disorders

In recent years, the vascular endothelium has gained attention as a key player in the initiation and development of pregnancy disorders. Endothelium acts as an endocrine organ that preserves the homeostatic balance by responding to changes in metabolic status. However, in metabolic disorders, endothelial cells adopt a dysfunctional function, losing their normal responsiveness. During pregnancy, several metabolic changes occur, in which endothelial function decisively participates. Similarly, when pregnancy metabolic disorders occur, endothelial dysfunction plays a key role in pathogenesis. This review outlines the main findings regarding endothelial dysfunction in three main metabolic pathological conditions observed during pregnancy: gestational diabetes, hypertensive disorders, and obesity and hyperlipidemia. Organ, histological and cellular characteristics were thoroughly described. Also, we focused in discussing the underlying molecular mechanisms involved in the cellular signaling pathways that mediate responses in these pathological conditions

ICAR: endoscopic skull‐base surgery

n/

Involvement of A2B adenosine receptors as anti-inflammatory in gestational diabesity

Pregnant women that are obese may develop gestational diabetes mellitus (GDM) configuring a new metabolic condition referred to as gestational diabesity. The metabolic alterations seen in gestational diabesity include a combination of an exacerbated pro-inflammatory state and fetoplacental endothelial dysfunction. Also, gestational diabesity associates with supra-physiological extracellular concentration of adenosine in the foetoplacental blood. Since adenosine plays a central role in the inflammatory response in GDM and obesity, it is likely that this nucleoside will play a similar role in gestational diabesity. However, the effect of adenosine in the foetoplacental vasculature in this condition is not yet addressed. Adenosine exerts its biological actions via four adenosine receptors. Activation of A adenosine receptors (AAR) subtype associates with an anti-inflammatory response in several tissue and diseases. In tissues from pregnant women with GDM, there is an overexpression of AAR, and higher mRNA expression of ADORA2B (for AAR) was shown to correlate with hyperglycaemia and oxidative stress. AAR shows low affinity for adenosine (micromolar) and its activation results in triggering intracellular signalling cascades lowering the inflammatory response. This phenomenon requires a high level of extracellular adenosine in diseases of pregnancy such as GDM or gestational diabesity. In this review, we focused on the role of AAR involvement in the biological actions of adenosine on inflammation in the foetoplacental vasculature in gestational diabesity. Some factors including oxidative stress and hypoxia in this phenomenon are discussed

Extracellular vesicles in obesity and diabetes mellitus

Cell-to-cell communication happens via diverse mechanisms including the synthesis, release and transfer to target cells of extracellular vesicles (EVs). EVs include nanovesicles (i.e., exosomes) and microvesicles, including apoptotic bodies. The amount and cargo of released EVs, which consist of microRNAs (miRNAs), mRNA, proteins, DNA, among other molecules, are altered in obesity and diabetes mellitus. EVs from these diseases show with altered cargo including several miRNAs and the enrichment with molecules involved in inflammation, immune efficiency, and cell activation. The role of EVs in obesity regards with adipocytes-released vesicles that may end in a systemic insulin resistance. In diabetes mellitus, the exosomes cargo may signal to transform a normal phenotype into a diabetic phenotype in endothelial cells. The evidence of EVs as modulators of cell function is increasing; however, it is still unclear whether exosomes or microvesicles are a trustable and useful marker for the diagnose or early detection of obesity or diabetes mellitus. In this review, we summarise the reported information regarding EVs involvement in obesity, T1 and T2 diabetes mellitus, and gestational diabetes mellitus. We emphasise the fact that studies addressing a potential effect of obesity or diabetes mellitus on cell function and the severity of the diseases are done in patients suffering simultaneously with both of these diseases, i.e., diabesity. Unfortunately, the lack of information regarding the biological effects and the potential involved mechanisms makes difficult to understand the role of the EVs as a marker of these and perhaps other diseases

Role of insulin, adenosine, and adipokine receptors in the foetoplacental vascular dysfunction in gestational diabetes mellitus

Gestational diabetes mellitus (GDM) is a disease of pregnancy associated with maternal and foetal hyperglycaemia and altered foetoplacental vascular function. Human foetoplacental microvascular and macrovascular endothelium from GDM pregnancy show increased maximal L-arginine transport capacity via the human cationic amino acid transporter 1 (hCAT-1) isoform and nitric oxide (NO) synthesis by the endothelial NO synthase (eNOS). These alterations are paralleled by lower maximal transport activity of the endogenous nucleoside adenosine via the human equilibrative nucleoside transporter 1 (hENT1) and activation of adenosine receptors. A causal relationship has been described for adenosine-activation of A adenosine receptors, hCAT-1, and eNOS activity (i.e. the Adenosine/L-Arginine/Nitric Oxide, ALANO, signalling pathway). Insulin restores these alterations in GDM via activation of insulin receptor A (IR-A) form in the macrovascular but IR-A and IR-B forms in the microcirculation of the human placenta. Adipokines are secreted from adipocytes influencing the foetoplacental metabolic and vascular function. Various adipokines are dysregulated in GDM, with adiponectin and leptin playing major roles. Abnormal plasma concentration of these adipokines and the activation or their receptors are involved in the pathophysiology of GDM. However, involvement of adipokines, adenosine, and insulin receptors and membrane transporters in the aetiology of this disease of pregnancy is unknown. This review focuses on the pathophysiology of insulin and adenosine receptors and L-arginine and adenosine membranes transporters giving an overview of the key adipokines leptin and adiponectin in the foetoplacental vasculature in GDM. This article is part of a Special Issue entitled: Membrane Transporters and Receptors in Pregnancy Metabolic Complications edited by Luis Sobrevia