Emerging Protein Biomarkers for the Diagnosis or Prediction of Gestational Diabetes-A Scoping Review.

Introduction: Gestational diabetes (GDM), defined as hyperglycemia with onset or initial recognition during pregnancy, has a rising prevalence paralleling the rise in type 2 diabetes (T2DM) and obesity. GDM is associated with short-term and long-term consequences for both mother and child. Therefore, it is crucial we efficiently identify all cases and initiate early treatment, reducing fetal exposure to hyperglycemia and reducing GDM-related adverse pregnancy outcomes. For this reason, GDM screening is recommended as part of routine pregnancy care. The current screening method, the oral glucose tolerance test (OGTT), is a lengthy, cumbersome and inconvenient test with poor reproducibility. Newer biomarkers that do not necessitate a fasting sample are needed for the prompt diagnosis of GDM. The aim of this scoping review is to highlight and describe emerging protein biomarkers that fulfill these requirements for the diagnosis of GDM. Materials and Methods: This scoping review was conducted according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines for scoping reviews using Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing & Allied Health Literature (CINAHL), PubMed, Embase and Web of Science with a double screening and extraction process. The search included all articles published in the literature to July 2020. Results: Of the 3519 original database citations identified, 385 were eligible for full-text review. Of these, 332 (86.2%) were included in the scoping review providing a total of 589 biomarkers studied in relation to GDM diagnosis. Given the high number of biomarkers identified, three post hoc criteria were introduced to reduce the items set for discussion: we chose only protein biomarkers with at least five citations in the articles identified by our search and published in the years 2017-2020. When applied, these criteria identified a total of 15 biomarkers, which went forward for review and discussion. Conclusions: This review details protein biomarkers that have been studied to find a suitable test for GDM diagnosis with the potential to replace the OGTT used in current GDM screening protocols. Ongoing research efforts will continue to identify more accurate and practical biomarkers to take GDM screening and diagnosis into the 21st century.

THG113.31, a specific PGF2alpha receptor antagonist, induces human myometrial relaxation and BKCa channel activation.

BACKGROUND: PGF2alpha exerts a significant contractile effect on myometrium and is central to human labour. THG113.31, a specific non-competitive PGF2alpha receptor (FP) antagonist, exerts an inhibitory effect on myometrial contractility. The BKCa channel is ubiquitously encountered in human uterine tissue and plays a significant role in modulating myometrial cell membrane potential and excitability. The objective of this study was to investigate potential BKCa channel involvement in the response of human myometrium to THG113.31. METHODS: Single and whole-cell electrophysiological BKCa channel recordings from freshly dispersed myocytes, were investigated in the presence and absence of THG113.31. Functional studies investigated the effects of THG113.31 on isolated spontaneous myometrial contractions, in the presence and absence of the BKCa channel blocker, iberiotoxin. RESULTS: Single channel recordings identified the BKCa channel as a target of THG113.31. THG113.31 significantly increased the open state probability of these channels [control 0.023+/-0.006; 10 microM THG113.31 0.087+/-0.012 (P = 0.009); and 50 microM THG113.31 0.1356+/-0.018 (P = 0.001)]. In addition, THG113.31 increased whole-cell BKCa currents over a range of membrane potentials, and this effect was reversed by 100 nanoM IbTX. Isometric tension studies demonstrated that THG113.31 exerted a significant concentration-dependent relaxant effect on human myometrial tissue and pre-incubation of strips with IbTX abolished this effect on spontaneously occurring contractions. CONCLUSION: These data suggests that activation of the BKCa channel may contribute, at least partially, to the uterorelaxant effect of THG113.31.

Functional coupling of beta3-adrenoceptors and large conductance calcium-activated potassium channels in human uterine myocytes.

CONTEXT: Beta3-adrenoreceptor modulation in human myometrium during pregnancy is linked functionally to myometrial inhibition. Maxi-K+ channels (BK(Ca)) play a significant role in modulating cell membrane potential and excitability. OBJECTIVE: This study was designed to investigate the potential involvement of BK(Ca) channel function in the response of human myometrium to beta3-adrenoceptor activation. DESIGN: Single and whole-cell electrophysiological BK(Ca) channel recordings from freshly dispersed myocytes were obtained in the presence and absence of BRL37344, a specific beta3-adrenoreceptor agonist. The in vitro effects of BRL37344 on isolated myometrial contractions, in the presence and absence of the specific BK(Ca) channel blocker, iberiotoxin (IbTX), were investigated. SETTING: The study was carried out at the Clinical Science Institute. PATIENTS OR OTHER PARTICIPANTS: Myometrial biopsies were obtained at elective cesarean delivery. INTERVENTION: No intervention was applied. MAIN OUTCOME MEASURES: Open state probability of single channel recordings, whole cell currents, and myometrial contractile activity were measured. RESULTS: Single-channel recordings identified the BK(Ca) channel as a target of BRL37344. BRL37344 significantly increased the open state probability of this channel in a concentration-dependent manner (control 0.031 +/- 0.004; 50 microM BRL37344 0.073 +/- 0.005 (P < 0.001); and 100 microM BRL37344 0.101 +/- 0.005 (P < 0.001). This effect was completely blocked after preincubation of the cells with 1 microM bupranolol, a nonspecific beta-adrenoreceptor blocker, or 100 nM SR59230a, a specific beta3-adrenoreceptor antagonist. In addition, BRL37344 increased whole-cell currents over a range of membrane potentials, and this effect was reversed by 100 nM IbTX. In vitro isometric tension studies demonstrated that BRL37344 exerted a significant concentration-dependent relaxant effect on human myometrial tissue (P < 0.05), and preincubation of these strips with IbTX attenuated this effect on both spontaneous and oxytocin-induced contractions (44.44 and 57.84% at 10(-5) M, respectively). CONCLUSIONS: These findings outline that activation of the BK(Ca) channel may explain the potent uterorelaxant effect of beta3-adrenoreceptor agonists.

Human chorionic gonadotrophin relaxation of human pregnant myometrium and activation of the BKCa channel.

The uterorelaxant effect of human chorionic gonadotropin (hCG) is regarded as an important mediator in maintenance of uterine quiescence during pregnancy with clinical potential for tocolysis, the mechanisms of which are unknown. The large conductance calcium-activated K(+) channel (BK(Ca)) is ubiquitously encountered in human uterine tissue and plays a significant role in modulating myometrial cell membrane potential and excitability. The objective of this study was to investigate the involvement of BK(Ca) channel function in the response of human myometrial cells to hCG. Single electrophysiological BK(Ca) channel recordings from freshly dispersed myocytes were obtained in the presence and absence of increasing hCG concentrations. Isometric tension studies, investigating the effects of hCG on isolated myometrial contractions, in the presence and absence of the BK(Ca) channel blocker, iberiotoxin, were performed. The hCG significantly increased the open-state probability of these channels in a concentration-dependent manner [control 0.036 +/- 0.01; 1 IU/ml hCG 0.065 +/- 0.014 (P = 0.262); 10 IU/ml hCG 0.111 +/- 0.009 (P = 0.001); and 100 IU/ml hCG 0.098 +/- 0.004 (P = 0.007)]. In vitro functional studies demonstrated that hCG exerted a significant concentration-dependent relaxant effect on human myometrial tissue. This effect was significantly attenuated by preincubation with iberiotoxin (P < 0.05). These findings outline that activation of BK(Ca) channel activity may explain the potent uterorelaxant effect of hCG.