Socioeconomic deprivation as measured by the index of multiple deprivation and its association with low sex hormone binding globulin in women

ACKNOWLEDGEMENTS M.L., I.L. and A.H.H. participated in the study concept and design, acquisition of data, study analysis, interpretation of data, drafting of the manuscript. D.M. provided statistical expertise. R.D., A.J.H., and A.F. participated in the interpretation of data and critical revision of the manuscript.Peer reviewedPublisher PD

Methylation status of exon IV of the brain-derived neurotrophic factor (BDNF)-encoding gene in patients with non-diabetic hyperglycaemia (NDH) before and after a lifestyle intervention

BDNF signalling in hypothalamic neuronal circuits is thought to regulate mammalian food intake. In light of this, we investigated how a lifestyle intervention influenced serum levels and DNA methylation of BDNF gene in fat tissue and buffy coat of NDH individuals. In total, 20 participants underwent anthropometric measurements/fasting blood tests and adipose tissue biopsy pre-/post-lifestyle (6 months) intervention. DNA was extracted from adipose tissue and buffy coat, bisulphite converted, and pyrosequencing was used to determine methylation levels in exon IV of the BDNF gene. RNA was extracted from buffy coat for gene expression analysis and serum BDNF levels were measured by ELISA. No differences were found in BDNF serum levels, but buffy coat mean BDNF gene methylation decreased post-intervention. There were correlations between BDNF serum levels and/or methylation and cardiometabolic markers. (i) Pre-intervention: for BDNF methylation, we found positive correlations between mean methylation in fat tissue and waist-hip ratio, and negative correlations between mean methylation in buffy coat and weight. (ii) Post-intervention: we found correlations between BDNF mean methylation in buffy coat and HbA1c, BDNF methylation in buffy coat and circulating IGFBP-2, and BDNF serum and insulin. Higher BDNF % methylation levels are known to reduce BNDF expression. The fall in buffy coat mean BDNF methylation plus the association between lower BDNF methylation (so potentially higher BDNF) and higher HbA1c and serum IGFBP-2 (as a marker of insulin sensitivity) and between lower serum BDNF and higher circulating insulin are evidence for the degree of BDNF gene methylation being implicated in insulinisation and glucose homeostasis, particularly after lifestyle change in NDH individuals

Bariatric Surgery Leads to a Reduction in Antibodies to Apolipoprotein A-1: a Prospective Cohort Study

Purpose: Autoantibodies against apolipoprotein A-1 have been associated with cardiovascular disease, poorer CV outcomes and all-cause mortality in obese individuals. The impact of bariatric surgery (BS) on the presence of circulating anti-apoA-1 IgG antibodies is unknown. This study aimed to determine the effect of bariatric surgery on auto-antibodies titres against Apolipoprotein A-1 (anti-apoA-1 IgG), looking for changes associated with lipid parameters, insulin resistance, inflammatory profile and percentage of excess body mass index loss (%EBMIL).Materials and methods: We assessed 55 patients (40 women) before, 6 and 12 months post-operatively. Baseline and post-operative clinical history and measurements of body mass index (BMI), serum cholesterol, triglycerides, high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), apoA-1, highly sensitive C-reactive protein (hsCRP), fasting glucose (FG), glycated haemoglobin (HbA1c) and HOMA-IR were taken at each point. Human anti-apoA-1 IgG were measured by ELISA.Results: The mean age of participants was 50 years. BS significantly improved BMI, %EBMIL triglycerides, HDL-C, apoA-1, hsCRP, HBA1c, FG and HOMA-IR. Baseline anti-apoA-1 IgG seropositivity was 25% and was associated with lower apoA-1 and higher hsCRP levels. One year after BS, anti-apoA-1 IgG seropositivity decreased to 15% (p = 0.007) and median anti-apoA-1 IgG values decreased from 0.70 (0.56-0.84) to 0.47 (0.37-0.61) AU (p Conclusion: Bariatric surgery results in significant reduction in anti-apoA-1 IgG levels, which may adversely influence weight loss. The exact mechanisms underpinning these results are elusive and require further study before defining any clinical recommendations.</p

Study of the common genetic background for rheumatoid arthritis and systemic lupus erythematosus

BACKGROUND: Evidence is beginning to emerge that there may be susceptibility loci for rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) that are common to both diseases. OBJECTIVE: To investigate single nucleotide polymorphisms that have been reported to be associated with SLE in a UK cohort of patients with RA and controls. METHODS: 3962 patients with RA and 9275 controls were included in the study. Eleven SNPs mapping to confirmed SLE loci were investigated. These mapped to the TNFSF4, BANK1, TNIP1, PTTG1, UHRF1BP1, ATG5, JAZF1, BLK, KIAA1542, ITGAM and UBE2L3 loci. Genotype frequencies were compared between patients with RA and controls using the trend test. RESULTS: The SNPs mapping to the BLK and UBE2L3 loci showed significant evidence for association with RA. Two other SNPs, mapping to ATG5 and KIAA1542, showed nominal evidence for association with RA (p=0.02 and p=0.02, respectively) but these were not significant after applying a Bonferroni correction. Additionally, a significant global enrichment in carriage of SLE alleles in patients with RA compared with controls (p=9.1×10(-7)) was found. Meta-analysis of this and previous studies confirmed the association of the BLK and UBE2L3 gene with RA at genome-wide significance levels (p<5×10(-8)). Together, the authors estimate that the SLE and RA overlapping loci, excluding HLA-DRB1 alleles, identified so far explain ∼5.8% of the genetic susceptibility to RA as a whole. CONCLUSION: The findings confirm the association of the BLK and UBE2L3 loci with RA, thus adding to the list of loci showing overlap between RA and SLE

Changes in the Proteome Profile of People Achieving Remission of Type 2 Diabetes after Bariatric Surgery

From MDPI via Jisc Publications RouterHistory: accepted 2021-08-17, pub-electronic 2021-08-18Publication status: PublishedBariatric surgery (BS) results in metabolic pathway recalibration. We have identified potential biomarkers in plasma of people achieving type 2 diabetes mellitus (T2DM) remission after BS. Longitudinal analysis was performed on plasma from 10 individuals following Roux-en-Y gastric bypass (n = 7) or sleeve gastrectomy (n = 3). Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was done on samples taken at 4 months before (baseline) and 6 and 12 months after BS. Four hundred sixty-seven proteins were quantified by SWATH-MS. Principal component analysis resolved samples from distinct time points after selection of key discriminatory proteins: 25 proteins were differentially expressed between baseline and 6 months post-surgery; 39 proteins between baseline and 12 months. Eight proteins (SHBG, TF, PRG4, APOA4, LRG1, HSPA4, EPHX2 and PGLYRP) were significantly different to baseline at both 6 and 12 months post-surgery. The panel of proteins identified as consistently different included peptides related to insulin sensitivity (SHBG increase), systemic inflammation (TF and HSPA4—both decreased) and lipid metabolism (APOA4 decreased). We found significant changes in the proteome for eight proteins at 6- and 12-months post-BS, and several of these are key components in metabolic and inflammatory pathways. These may represent potential biomarkers of remission of T2DM

The Methyltransferase WBSCR22/Merm1 Enhances Glucocorticoid Receptor Function and Is Regulated in Lung Inflammation and Cancer

Glucocorticoids (GC) regulate cell fate and immune function. We identified the metastasis-promoting methyltransferase, metastasis-related methyltransferase 1 (WBSCR22/Merm1) as a novel glucocorticoid receptor (GR) regulator relevant to human disease. Merm1 binds the GR co-activator GRIP1 but not GR. Loss of Merm1 impaired both GR transactivation and transrepression by reducing GR recruitment to its binding sites. This was accompanied by loss of GR-dependent H3K4Me3 at a well characterized promoter. Inflammation promotes GC resistance, in part through the actions of TNFα and IFNγ. These cytokines suppressed Merm1 protein expression by driving ubiquitination of two conserved lysine residues. Restoration of Merm1 expression rescued GR transactivation. Cytokine suppression of Merm1 and of GR function was also seen in human lung explants. In addition, striking loss of Merm1 protein was observed in both inflammatory and neoplastic human lung pathologies. In conclusion, Merm1 is a novel regulator of chromatin structure affecting GR recruitment and function, contributing to loss of GC sensitivity in inflammation, with suppressed expression in pulmonary disease

Ultradian Cortisol Pulsatility Encodes a Distinct, Biologically Important Signal

Cortisol is released in ultradian pulses. The biological relevance of the resulting fluctuating cortisol concentration has not been explored.Determination of the biological consequences of ultradian cortisol pulsatility.A novel flow through cell culture system was developed to deliver ultradian pulsed or continuous cortisol to cells. The effects of cortisol dynamics on cell proliferation and survival, and on gene expression were determined. In addition, effects on glucocorticoid receptor (GR) expression levels and phosphorylation, as a potential mediator, were measured.Pulsatile cortisol caused a significant reduction in cell survival compared to continuous exposure of the same cumulative dose, due to increased apoptosis. Comprehensive analysis of the transcriptome response by microarray identified genes with a differential response to pulsatile versus continuous glucocorticoid delivery. These were confirmed with qRT-PCR. Several transcription factor binding sites were enriched in these differentially regulated target genes, including CCAAT-displacement protein (CDP). A CDP regulated reporter gene (MMTV-luc) was, as predicted, also differentially regulated by pulsatile compared to continuous cortisol delivery. Importantly there was no effect of cortisol delivery kinetics on either GR expression, or activation (GR phosphoSer(211)).Cortisol oscillations exert important effects on target cell gene expression, and phenotype. This is not due to differences in cumulative cortisol exposure, or either expression, or activation of the GR. This suggests a novel means to regulate GR function

Genetically defined favourable adiposity is not associated with a clinically meaningful difference in clinical course in people with type 2 diabetes but does associate with a favourable metabolic profile

From Wiley via Jisc Publications RouterHistory: received 2020-07-23, rev-recd 2021-01-18, accepted 2021-01-21, pub-electronic 2021-02-11, pub-print 2021-09Article version: VoRPublication status: PublishedFunder: Diabetes UK; Id: http://dx.doi.org/10.13039/501100000361; Grant(s): 17/0005594Funder: European Research Council; Grant(s): 323195Abstract: Aims: Change in weight, HbA1c, lipids, blood pressure and cardiometabolic events over time is variable in individuals with type 2 diabetes. We hypothesised that people with a genetic predisposition to a more favourable adiposity distribution could have a less severe clinical course/progression. Methods: We involved people with type 2 diabetes from two UK‐based cohorts: 11,914 individuals with GP follow‐up data from the UK Biobank and 723 from Salford. We generated a ‘favourable adiposity’ genetic score and conducted cross‐sectional and longitudinal studies to test its association with weight, BMI, lipids, blood pressure, medication use and risk of myocardial infarction and stroke using 15 follow‐up time points with 1‐year intervals. Results: The ‘favourable adiposity’ genetic score was cross‐sectionally associated with higher weight (effect size per 1 standard deviation higher genetic score: 0.91 kg [0.59,1.23]) and BMI (0.30 kg/m2 [0.19,0.40]), but higher high‐density lipoprotein (0.02 mmol/L [0.01,0.02]) and lower triglycerides (−0.04 mmol/L [−0.07, −0.02]) in the UK Biobank at baseline, and this pattern of association was consistent across follow‐up. There was a trend for participants with higher ‘favourable adiposity’ genetic score to have lower risk of myocardial infarction and/or stroke (odds ratio 0.79 [0.62, 1.00]) compared to those with lower score. A one standard deviation higher score was associated with lower odds of using lipid‐lowering (0.91 [0.86, 0.97]) and anti‐hypertensive medication (0.95 [0.91, 0.99]). Conclusions: In individuals with type 2 diabetes, having more ‘favourable adiposity’ alleles is associated with a marginally better lipid profile long‐term and having lower odds of requiring lipid‐lowering or anti‐hypertensive medication in spite of relatively higher adiposity