Circulating vaspin is unrelated to insulin sensitivity in a cohort of nondiabetic humans

Objective: To study the association of vaspin with glucose metabolism. Design: Cross-sectional and intervention study. Subjects and methods: The association of serum vaspin with metabolic and anthropometric characteristics was investigated in 108 volunteers. Euglycemic–hyperinsulinemic clamps (EHC) were performed in 83 of the participants. Changes of circulating vaspin levels were additionally studied in a crossover study using 300 min EHC with lipid versus saline infusion (n=10). Results: Neither glucose tolerance status nor insulin sensitivity, both as measured using EHCs and using homeostasis model assessment for insulin resistance (HOMA-IR), was significantly associated with serum vaspin in the cross-sectional study. Furthermore, there was no effect of short-term lipid-induced insulin resistance due to a 300 min intravenous lipid challenge on circulating vaspin. However, circulating vaspin levels were significantly elevated in women using oral contraceptives (OC), both compared to women without OC intake (1.17±0.26 vs 0.52±0.09 ng/ml, P=0.02) and males (1.17±0.26 vs 0.29±0.04 ng/ml, P=0.01). After exclusion of OC using females and stratification according to body mass index (BMI), a significant sexual dimorphism in subjects with a BMI <25 kg/m2 was observed (males 0.21±0.04 ng/ml versus females 0.70±0.16 ng/ml, P=0.009). Conclusion: Our results support the existence of a sexual dimorphism regarding circulating vaspin. The lack of an association of serum vaspin with HOMA-IR and M value indicates, however, no major role for vaspin concerning insulin sensitivity in nondiabetic humans

The “Road” to Malignant Transformation from Endometriosis to Endometriosis-Associated Ovarian Cancers (EAOCs): An mTOR-Centred Review

Data Availability Statement: No extra data is generated in this review article.Ovarian cancer is an umbrella term covering a number of distinct subtypes. Endometrioid and clear-cell ovarian carcinoma are endometriosis-associated ovarian cancers (EAOCs) frequently arising from ectopic endometrium in the ovary. The mechanistic target of rapamycin (mTOR) is a crucial regulator of cellular homeostasis and is dysregulated in both endometriosis and endometriosis-associated ovarian cancer, potentially favouring carcinogenesis across a spectrum from benign disease with cancer-like characteristics, through an atypical phase, to frank malignancy. In this review, we focus on mTOR dysregulation in endometriosis and EAOCs, investigating cancer driver gene mutations and their potential interaction with the mTOR pathway. Additionally, we explore the complex pathogenesis of transformation, considering environmental, hormonal, and epigenetic factors. We then discuss postmenopausal endometriosis pathogenesis and propensity for malignant transformation. Finally, we summarize the current advancements in mTOR-targeted therapeutics for endometriosis and EAOCs.This research received no external funding

The prevalence of obstructive sleep apnoea in women with polycystic ovary syndrome:a systematic review and meta-analysis

Background: Obesity is a common risk factor for polycystic ovary syndrome (PCOS) and obstructive sleep apnoea (OSA). Both PCOS and OSA are associated with increased risk of type 2 diabetes and cardiovascular disease. Hence, it is important to determine the burden of OSA in women with PCOS. Methods: We searched electronic databases (MEDLINE, Embase, CINAHL, PsycINFO, Scopus, Web of Science, OpenGrey, CENTRAL), conference abstracts, and reference lists of relevant articles, up to January 2019. No restriction for language or publication status. Studies that examined the presence of OSA in women with PCOS using polysomnography and/or level III devices were eligible for inclusion. Results: Seventeen studies involving 648 participants were included. Our meta-analysis showed that 35.0% (95% CI 22.2–48.9%) of women with PCOS had OSA. This prevalence was not affected by variation in PCOS definition between studies. Approximately one-tenth of the variation in OSA prevalence was related to differences in study population (higher in adults than adolescents and mixed populations), and around one-tenth was related to sample size (higher in smaller studies). OSA prevalence was markedly higher in obese versus lean women with PCOS, and in women with PCOS compared to controls (odds ratio = 3.83, 95% CI 1.43–10.24, eight studies, 957 participants (349 PCOS and 608 controls)). However, most of the studies were at high risk of selection bias, did not account for important confounders, included predominantly women with class II obesity, and were conducted in one country (USA). Conclusions: Future studies need to examine the true prevalence of OSA in a more representative sample of women with PCOS. Nevertheless, our results suggest that the prevalence of OSA in women with PCOS and obesity is high and clinicians should have a high index of suspicion of OSA in these women

Extracellular cardiac matrix biomarkers in patients with reduced ejection fraction heart failure as predictors of response to cardiac resynchronisation therapy: a systematic review.

OBJECTIVE: Cardiac resynchronisation therapy (CRT) is an effective therapy for selected patients with heart failure (HF); however, a significant non-response rate exists. We examined current evidence on extracellular cardiac matrix (ECM) biomarkers in predicting response following CRT. METHODS: Complete literature review of PubMed, Ovid SP MEDLINE, Cochrane Library and TRIP, reference lists, international cardiology conferences and ongoing studies between December 1999 and December 2015 conducted according to prospectively registered study selection and analysis criteria (PROSPERO:CRD42016025864) was performed. All observational and randomised control trials (RCT) were included if they tested prespecified ECM biomarkers' ability to predict CRT response. Risk of bias assessment and data extraction determined pooling of included studies was not feasible due to heterogeneity of the selected studies. RESULTS: A total of 217 studies were screened; six (five prospective cohort and one RCT substudy) were included in analysis with 415 participants in total. Study sizes varied (n=55-260), cohort characteristics contrasted (male: 67.8%-83.6%, ischaemic aetiology: 40.2%-70.3%) and CRT response definitions differed (three clinical/functional, three echocardiographic). Consistent observation in all ECM biomarker behaviour before and after CRT implantation was not observed between studies. Lower type I and type III collagen synthesis biomarkers (N-terminal propeptides of type I and III procollagens) expression demonstrated replicated ability to predict reverse left ventricular remodelling. CONCLUSION: Collagen synthesis biomarkers offer the most potential as ECM biomarkers for predicting CRT response. Heterogeneity between these studies was large and limited the ability to pool and compare results numerically. Use of different response definitions was one of the biggest challenges

Exercise interventions significantly reduce fasting insulin, but not fasting glucose, in women with polycystic ovary syndrome when compared with no intervention: A systematic review and meta-analysis

Aims: Polycystic ovary syndrome (PCOS) is a common condition that affects approximately 20% of reproductive‐aged women. PCOS is also associated with insulin resistance; women with PCOS are more insulin resistant than body mass index–matched controls. Methods: A systematic review was completed; randomised controlled trials that compared physical activity with control groups were evaluated in a meta‐analysis. Outcomes related to glucose homeostasis were analysed. Change from baseline to end of intervention values were reported as mean difference (MD) and 95% confidence intervals (CI). Results: There was evidence of a favourable effect of exercise on fasting insulin levels (MD −2.62 μIU/ml, CI −4.46 to −0.77; I2 = 92%; 236 participants, eight trials), but not for fasting blood glucose. Reductions in fasting insulin were found for all exercise modalities (aerobic, resistance or combined exercise), but were strongest in resistance training groups (MD −3.99 μIU/ml, CI −5.97 to −2.00; I2 = 54%; 50 participants, three trials). Change from baseline HOMA index also favoured exercise (MD −0.59, CI −1.02 to −0.17; I2 = 89%; 146 participants, seven trials) but evidence of effect was only present in aerobic exercise groups (MD −0.77, CI −1.28 to −0.26; I2 = 65%; 75 participants, four trials). Summary: Exercise, regardless of modality, reduces fasting insulin, but not fasting blood glucose, in women with PCOS compared with those receiving no intervention. However, a cautious approach should be adopted in interpreting these findings due to the wide CIs and evidence of considerable heterogeneity. Despite the statistically significant results, it is unclear if these improvements are clinically relevant

Home administration of lanreotide Autogel® by patients with acromegaly, or their partners, is safe and effective

Summary. Objective The introduction of ready-to-use lanreotide Autogel® has presented the possibility of patients receiving their acromegaly treatment at home. The objective of this study was to assess the ability of patients (or their partners) to administer repeat, unsupervised, injections of lanreotide Autogel without compromising efficacy or safety. Design Multicentre (10 UK regional endocrine centres), open-label, nonrandomised, controlled study. Patients elected either to receive/administer unsupervised home injections after injection technique training (Test group) or continued to receive injections from a healthcare professional (Control group). Patients received monthly injections of lanreotide Autogel® at their established dose. Effects were monitored for up to 40 weeks. Patients Thirty patients (15 per treatment group) with acromegaly treated with a stable dose of lanreotide Autogel® (60, 90 or 120 mg) for ≥ 4 months before screening. Measurements The main outcome measure was the proportion of patients/partners who successfully administered injections throughout the study. Results All Test group patients/partners qualified to administer injections. Fourteen of 15 patients fulfilled all criteria for successful administration of unsupervised injections (95% confidence interval, 70%–99%). Fourteen of 15 Test and 14/15 Control patients maintained growth hormone and IGF-1 control. Local injection tolerability was good for both treatment groups, and safety profiles were similar. All Test group patients continued with unsupervised injections after the study. Conclusions Patients with acromegaly or their partners were able to administer lanreotide Autogel® injections with no detrimental effect on efficacy and safety; therefore, unsupervised home injections are a viable alternative to healthcare professional injections for suitably motivated patients

Lower cerebrospinal fluid/plasma fibroblast growth factor 21 (FGF21) ratios and placental FGF21 production in gestational diabetes

Objectives: Circulating Fibroblast Growth Factor 21 (FGF21) levels are increased in insulin resistant states such as obesity, type 2 diabetes mellitus and gestational diabetes mellitus (GDM). In addition, GDM is associated with serious maternal and fetal complications. We sought to study human cerebrospinal fluid (CSF) and corresponding circulating FGF21 levels in women with gestational diabetes mellitus (GDM) and in age and BMI matched control subjects. We also assessed FGF21 secretion from GDM and control human placental explants. Design: CSF and corresponding plasma FGF21 levels of 24 women were measured by ELISA [12 GDM (age: 26–47 years, BMI: 24.3–36.3 kg/m2) and 12 controls (age: 22–40 years, BMI: 30.1–37.0 kg/m2)]. FGF21 levels in conditioned media were secretion from GDM and control human placental explants were also measured by ELISA. Results: Glucose, HOMA-IR and circulating NEFA levels were significantly higher in women with GDM compared to control subjects. Plasma FGF21 levels were significantly higher in women with GDM compared to control subjects [234.3 (150.2–352.7) vs. 115.5 (60.5–188.7) pg/ml; P<0.05]. However, there was no significant difference in CSF FGF21 levels in women with GDM compared to control subjects. Interestingly, CSF/Plasma FGF21 ratio was significantly lower in women with GDM compared to control subjects [0.4 (0.3–0.6) vs. 0.8 (0.5–1.6); P<0.05]. FGF21 secretion into conditioned media was significantly lower in human placental explants from women with GDM compared to control subjects (P<0.05). Conclusions: The central actions of FGF21 in GDM subjects maybe pivotal in the pathogenesis of insulin resistance in GDM subjects. The significance of FGF21 produced by the placenta remains uncharted and maybe crucial in our understanding of the patho-physiology of GDM and its associated maternal and fetal complications. Future research should seek to elucidate these points

Elevated Circulating Lactate Levels and Widespread Expression of Its Cognate Receptor, Hydroxycarboxylic Acid Receptor 1 (HCAR1), in Ovarian Cancer

Data Availability Statement: Upon request from principal investigator.Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/jcm12010217/s1, Figure S1: Gene expression of HCAR1 (hydroxycarboxylic acid receptor 1, HCAR1; formerly known as GPR81) from The Cancer Genome Atlas (TCGA) in cancer and normal tissues. Figure S2: Bland–Altman analysis of immunohistochemistry quantification scores. Table S1: Details of tissue microarray.Copyright © 2022 by the authors. Background: Augmented glycolysis in cancer cells is a process required for growth and development. The Warburg effect provides evidence of increased glycolysis and lactic acid fermentation in cancer cells. The lactate end-product of glycolysis is receiving growing traction for its role as a cell signalling molecule. Ovarian cancer (OvCa) is also characterised by altered glucose metabolism. We aim to explore circulating lactate levels in patients with high-grade serous OvCa (HGSOC) and to elucidate the expression of the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1) in OvCa. Methods: HCAR1 expression was detected in patient biopsy cores using immunohistochemistry, while lactate was measured from whole blood with a Biosen-C line clinic measuring system. Results: We noted significantly elevated lactate levels in OvCa patients (4.3 ± 1.9 mmol/L) compared with healthy controls (1.4 ± 0.6 mmol/L; p 75% expression in 100 patients), high protein expression was also recorded across all epithelial OvCa subtypes and ovarian normal adjacent tissue (NAT). Conclusions: Lactate monitoring is a simple, cost-efficient test that can offer point-of-care results. Our data suggest that the potential of circulating lactate as a screening biomarker in OvCa merits further research attention.Cancer Treatment & Research Trust and University Hospitals Coventry and Warwickshire NHS Trust (grant no. 12899)

Involvement of the Endocrine-Disrupting Chemical Bisphenol A (BPA) in Human Placentation

Background: Endocrine-disrupting chemicals (EDCs) are environmental chemicals/toxicants that humans are exposed to, interfering with the action of multiple hormones. Bisphenol A (BPA) is classified as an EDC with xenoestrogenic activity with potentially adverse effects in reproduction. Currently, a significant knowledge gap remains regarding the complete spectrum of BPA-induced effects on the human placenta. As such, the present study examined the effects of physiologically relevant doses of BPA in vitro. Methods: qRT-PCR, Western blotting, immunofluorescence, ELISA, microarray analyses, and bioinformatics have been employed to study the effects of BPA using nonsyncytialised (non-ST) and syncytialised (ST) BeWo cells. Results: Treatment with 3 nM BPA led to an increase in cell number and altered the phosphorylation status of p38, an effect mediated primarily via the membrane-bound estrogen receptor (GPR30). Nonbiased microarray analysis identified 1195 and 477 genes that were differentially regulated in non-ST BeWo cells, whereas in ST BeWo cells, 309 and 158 genes had altered expression when treated with 3 and 10 nM, respectively. Enriched pathway analyses in non-ST BeWo identified a leptin and insulin overlap (3 nM), methylation pathways (10 nM), and differentiation of white and brown adipocytes (common). In the ST model, most significantly enriched were the nuclear factor erythroid 2-related factor 2 (NRF2) pathway (3 nM) and mir-124 predicted interactions with cell cycle and differentiation (10 nM). Conclusion: Collectively, our data offer a new insight regarding BPA effects at the placental level, and provide a potential link with metabolic changes that can have an impact on the developing fetus.Isambard PhD Scholarship, Brunel University Londo