Metabolic consequences of obesity on the hypercoagulable state of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) women have a hypercoagulable state; however, whether this is intrinsically due to PCOS or, alternatively, a consequence of its metabolic complications is unclear. We determined plasma coagulation pathway protein levels in PCOS (n = 146) and control (n = 97) women recruited to a PCOS biobank. Circulating levels of a panel of 18 clotting pathway proteins were determined by Slow Off-rate Modified Aptamer-scan plasma protein measurement. Cohorts were age matched, though PCOS had elevated body mass index (p < 0.001), insulin (p < 0.001) and C-reactive protein (CRP) (p < 0.0001). Eight pro-coagulation proteins were elevated in PCOS: plasminogen activator inhibitor-1 (p < 0.0001), fibrinogen (p < 0.01), fibrinogen gamma chain (p < 0.0001), fibronectin (p < 0.01), von Willebrand factor (p < 0.05), D-dimer (p < 0.0001), P-selectin (p < 0.05), and plasma kallikrein (p < 0.001). However, two anticoagulant proteins, vitamin K-dependent protein-S (p < 0.0001) and heparin cofactor-II (p < 0.001) were elevated and prothrombin was decreased (p < 0.05). CRP, as a marker of inflammation, and insulin resistance (HOMA-IR) correlated with 11 and 6 of the clotting proteins, respectively (p < 0.05). When matched for BMI < 25 (16 PCOS, 53 controls) HOMA-IR remained elevated (p < 0.05) and heparin cofactor-II was increased (p < 0.05). In a multivariate analysis accounting for inflammation, insulin resistance and BMI, there was no correlation of PCOS with any of the coagulation proteins. The hypercoagulable state in PCOS is not intrinsic to the disease as it can be fully accounted for by BMI, inflammation and insulin resistance

Differing endometrial expression of calcium modulating transient receptor potential channels

Assisted reproductive techniques (ART) have increased the live birth success rate, but there is still a significant implantation failure rate. Epithelial cell calcium homeostasis is tightly regulated by mechanisms that include activation of the TRP channel superfamily of 9 families including TRPC (Canonical). TRPCs are located on the cell membrane and act as receptor-operated channels (ROC), whilst cytosolic localization of these channels indicates their role as store-operated channels (SOC): both ROCs and SOCs are key players in the regulation of intracellular calcium homeostasis. TRPC 1–4 and 6 expression in the bovine reproductive tract has been reported; these receptors exhibit hormone modulation and calcium dysregulation can lead to menstrual disturbances, suggesting that TRPC receptors may modulate calcium in the human endometrium and affect implantation and fertility.</p

Renin-angiotensin system overactivation in polycystic ovary syndrome, a risk for SARS-CoV-2 infection?

Background: The SARS-CoV-2 coronavirus gains entry to target cells via the angiotensin-converting enzyme 2 (ACE2) receptor present on cells in blood vessels, lungs, heart, intestines, and kidneys. Renin-Angiotensin System (RAS) overactivity has also been described in metabolic syndrome, type 2 diabetes (T2D) and obesity, conditions shared by women with polycystic ovary syndrome (PCOS) We hypothesized that RAS overactivity may be present in PCOS.Methods: We determined plasma levels of RAS-related proteins in a cohort of age matched control women (n = 97) and women with PCOS (n = 146). Plasma levels of RAS-related proteins (ACE2, Renin and Angiotensinogen (AGT)) were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement.Results: PCOS women had a higher BMI (p Conclusion: RAS proteins levels differed between PCOS and control women, suggesting that the insulin resistance inherent in PCOS may predispose these women to more severe COVID-19 infection.</p

Correction to: COVID-19 biomarkers for severity mapped to polycystic ovary syndrome

Following publication of the original article, the authors would like to correct the author group with regards to the equal contributions: Stephen L. Atkin and Alexandra E. Butler should be listed as joint senior authors. The author group has been updated above and the original article has been corrected

The relationship of soluble neuropilin-1 to severe COVID-19 risk factors in polycystic ovary syndrome

The SARS-CoV-2 coronavirus enters target cells via the angiotensin-converting enzyme 2 (ACE2) receptor; however, ACE2 expression does not match SARS-CoV-2 tissue load, suggesting additional co-factors are required for viral entry. Neuropilin-1 (NRP1) is such a co-factor that, when expressed alone shows minimal viral infectivity, but when co-expressed with ACE2 markedly increases viral infectivity. NRP1 is a transmembrane glycoprotein, which is expressed in endothelial cells, and serves as a receptor for vascular endothelial growth factor (VEGF), and both NRP1 and VEGF expression are increased in COVID-19 patients. SARS-CoV-2 uses the viral spike protein for cell entry, cleaving the protein that then attaches to NRP1. Therefore, tissues enriched for NRP1 have increased infectivity risk and subjects expressing increased NRP1 may have increased risk.</p

Metabolic comparison of polycystic ovarian syndrome and control women in Middle Eastern and UK Caucasian populations

To determine if metabolic characteristics differed in women with and without polycystic ovary syndrome (PCOS) between a Caucasian and Middle East population. Comparative cross-sectional analysis. Demographic and metabolic data from Middle Eastern women from Qatar Biobank (97 with PCOS, 622 controls) were compared to a Caucasian PCOS biobank in Hull UK (108 with PCOS, 69 controls). In both populations, PCOS women showed a worse cardiovascular risk profile of increased systolic and diastolic blood pressure, increased C-reactive protein (CRP), reduced HDL, insulin resistance as well as increased androgens compared to their respective controls without PCOS. UK women without PCOS had higher systolic and diastolic blood pressures, and increased testosterone results (p < 0.01) compared to Middle Eastern women without PCOS who had higher inflammatory markers (WBC and CRP), HDL and insulin resistance (p < 0.001). UK PCOS women had a higher body mass index, systolic and diastolic blood pressures, triglycerides (p < 0.01), whilst Middle Eastern PCOS women showed increased testosterone, free androgen index, HDL and CRP (P < 0.01). There was no difference in insulin or insulin resistance between the two PCOS cohorts. This study highlights ethnic population differences because, whilst cardiovascular risk indices were increased for both PCOS cohorts, this may be for different reasons: BMI, waist and hip measurements, systolic and diastolic blood pressure, and triglycerides were higher in the UK cohort whilst testosterone, HDL and CRP were higher in the Middle East population. Insulin resistance did not differ between the two PCOS populations despite differences in BMI

Do biomarkers of COVID-19 severity simply reflect a stress response in type 2 diabetes: biomarker response to hypoglycemia

Type 2 diabetes (T2D) is associated with high risk for acquiring SARSCov-2 infection, severe disease, acute respiratory distress syndrome and increased mortality. A recent publication reported five predictive COVID-19 severity markers that included CCL17 which was expressed in low levels in severe/critical patients at an early phase of infection; IFNλ, IL6, IP10, and CXCL9 values surged and then dropped suddenly before the development of severe disease requiring oxygen support. This suggested that CCL17 may be a useful first triage marker and the other reported proteins may help to predict severe disease onset.</p

Mapping of type 2 diabetes proteins to COVID-19 biomarkers: a proteomic analysis

To determine predictive biomarkers for COVID-19 disease and infection severity, large scale multi-omic analyses have been undertaken in patients with respiratory disease, with and without COVID-19 disease. Biomarkers involved in vessel damage, platelet degranulation, the coagulation cascade and the acute phase response were identified in COVID-19 disease and shown to differ further with increasing COVID-19 disease severity. However, differences in protein expression may differ between patients with type 2 diabetes (T2D) and controls and T2D patients may have altered markers of coagulation together with altered platelet function resulting in a prothrombotic propensity. Biomarkers, or a combination of biomarkers, specific for COVID-19 disease in T2D would necessarily be independent of differentially expressed proteins in T2D versus controls. Therefore, this proteomic analysis was undertaken in subjects with and without T2D to compare these with the COVID-19 disease-related proteomic biomarkers that have been identified by using shotgun proteomics followed by parallel reaction monitoring, and to determine if any of the protein changes were dependent on glycemia.</p

Vitamin D3 metabolite ratio as an indicator of vitamin D status and its association with diabetes complications

Background: Vitamin D deficiency is diagnosed by total serum 25-hydroxyvitamin D (25(OH)D) concentration and is associated with poor health and increased mortality; however, some populations have low 25(OH) D concentrations without manifestations of vitamin D deficiency. The Vitamin D Metabolite Ratio (VMR) has been suggested as a superior indicator of vitamin D status. Therefore, VMR was determined in a population with type 2 diabetes at high risk for vitamin D deficiency and correlated with diabetic complications.Research design and methods: Four hundred sisty patients with type 2 diabetes (T2D) were recruited, all were vitamin D3 supplement naive. Plasma concentration of 25-hydroxyvitamin D3 (25(OH)D3) and its metabolites 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) and its epimer, 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3), were measured by LC-MS/MS analysis. VMR-1 was calculated as a ratio of 24,25(OH)2D3:25(OH)D3; VMR-2 as a ratio of 1,25(OH)2D3:25(OH)D3; VMR-3 was calculated as a ratio of 3-epi-25(OH)D3: 25(OH)D3. RESULTS: An association means that there were significant differences between the ratios found for those with versus those without the various diabetic complications studied. VMR-1 was associated with diabetic retinopathy (p = 0.001) and peripheral artery disease (p = 0.012); VMR-2 associated with hypertension (p Conclusions: In this cross sectional study, whilst not causal, VMR-2 was shown to be the superior predictor of diabetic and cardiovascular complications though not demonstrative of causality in this cross-sectional study population over VMR-1, VMR-3 and the individual vitamin D concentration measurements; VMR-2 associated with both microvascular and cardiovascular indices and therefore may have utility in predicting the development of diabetic complications.</p

Relationship between total vitamin D metabolites and complications in patients with type 2 diabetes

In our previous study, it was shown that endogenous vitamin D3 and its metabolites are associated with diabetic microvascular complications and cardiovascular risk factors. The aim of the present study was to determine if the relationship between total vitamin D (vitamin D2 supplements plus endogenous vitamin D3) was a better predictor of complications in type 2 diabetes (T2DM). A total of 460 patients with T2DM participated in the present cross-sectional study. Plasma levels of total vitamin D and its metabolites (1,25-dihydroxyvitamin D (1,25(OH)D), 25-hydroxyvitamin D (25(OH)D) and 24,25-dihydroxyvitamin D (24,25(OH)D) were measured by isotope-dilution liquid chromatography tandem mass spectrometry analysis. 1,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 were associated with diabetic retinopathy and coronary artery disease, but total 1,25-dihydroxyvitamin D and total 25-hydroxyvitamin D levels were not statistically associated with any complications. Total 1,25-dihydroxyvitamin D showed the same positive association as 1,25-dihydroxyvitamin D3 for hypertension and dyslipidemia, and total 25-hydroxyvitamin D showed the same positive association as 25-hydroxyvitamin D3 for dyslipidemia. Total 24,25-dihydroxyvitamin D showed the same positive association only with dyslipidemia as did 24,25-dihydroxyvitamin D3. However, total 25-hydroxyvitamin D was associated with hypertension, whereas 25-hydroxyvitamin D3 was not. Vitamin D3 metabolites were associated with diabetic retinopathy, whereas total vitamin D levels were not, suggesting that endogenous vitamin D3 metabolites are a better measure of diabetic microvascular complications. However, both total vitamin D and vitamin D3 metabolites were associated with cardiovascular risk factors in patients with type 2 diabetes.<br