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Context Patients with active acromegaly present a decreased adipose tissue (AT) mass, and short-term studies show that treatment leads to AT depot-specific gain. However, it remains unclear if the increase is persistent in the long-term perspective and/or is sex-dependent. Design To characterize the depot-specific changes of AT after treatment of acromegaly and identify contributing factors. Methods Adipose tissue, including visceral (VAT), subcutaneous (SAT), and total (TAT), and android to gynoid ratio (A/G ratio) were measured by dual energy X-ray absorptiometry at diagnosis (n = 62), and after treatment at short-term (median (IQR) 1.9 (1.5-2.3)) and long-term 5.5 (3.9-9.5) years, and correlated to clinical and biochemical measurements. Growth hormone (GH), insulin-like growth factor 1 (IGF-1), glucose and HbA1c levels, gonadal status, and the presence of diabetes mellitus were recorded. Remission status was assessed at the long-term visit (IGF-1/ULN ≤ 1.3). Differences in the temporal course of AT from baseline to short- and long-term follow-up according to sex, diabetes, gonadal, and remission status were evaluated by mixed model analysis, adjusted for age. Results Despite a stable body mass index, VAT and A/G ratio increased at both time points, whereas SAT mainly increased at short-term, plateauing afterwards (P <.05 for all). Visceral adipose tissue and A/G ratio were higher in men (P =.035 and P <.001), and the A/G ratio increased more than in women (P =.003). Glucose and HbA1c decreased short-term (P <.05) and remained stable at long-term. The increase in AT depots correlated with the decrease of disease activity at long-term. Remission status had no effect on changes in AT mass during follow-up. Conclusion Treatment of acromegaly leads to an increase in AT mass in a depot- and sex-specific manner both at short-term and long-term follow-up. Glucose metabolism improves rapidly after disease control and persists. [ABSTRACT FROM AUTHOR]

Background and Hypothesis Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. Study Design We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. Study Results Our main findings were: (1) higher levels of sMAdCAM-1 (P =.002), I-FABP (P = 7.6E−11), CCL25 (P = 9.6E−05) and LBP (P = 2.6E−04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E−04) were observed in SCZ and I-FABP (P = 2.5E−10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. Conclusions Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation. [ABSTRACT FROM AUTHOR]

Background Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. Methods We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. Results Plasma APRIL level was significantly lower across all patient groups compared to HC (P <.001; Cohen's d = 0.33), and in SCZ compared to HC (P <.001; d = 0.28) and in BIP compared to HC (P <.001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P =.017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P =.040; d = 0.12) and SCZ (P =.027; d = 0.10). Conclusions These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders. [ABSTRACT FROM AUTHOR]

Objective: Hyperglycaemia during pregnancy increases the risk of adverse health outcomes in mother and child, but the genetic aetiology is scarcely studied. Our aims were to (1) assess the overlapping genetic aetiology between the pregnant and non-pregnant population and (2) assess the importance of genome-wide polygenic contributions to glucose traits during pregnancy, by exploring whether genetic risk scores (GRSs) for fasting glucose (FG), 2-h glucose (2hG), type 2 diabetes (T2D) and BMI in non-pregnant individuals were associated with glucose measures in pregnant women. Methods: We genotyped 529 Norwegian pregnant women and constructed GRS from known genome-wide significant variants and SNPs weakly associated (p> 5 × 10-8) with FG, 2hG, BMI and T2D from external genome-wide association studies (GWAS) and examined the association between these scores and glucose measures at gestational weeks 14-16 and 30-32. We also performed GWAS of FG, 2hG and shape information from the glucose curve during an oral glucose tolerance test (OGTT). Results: GRSFG explained similar variance during pregnancy as in the non-pregnant population (~5%). GRSBMI and GRST2D explained up to 1.3% of the variation in the glucose traits in pregnancy. If we included variants more weakly associated with these traits, GRS2hG and GRST2D explained up to 2.4% of the variation in the glucose traits in pregnancy, highlighting the importance of polygenic contributions. Conclusions: Our results suggest overlap in the genetic aetiology of FG in pregnant and non-pregnant individuals. This was less apparent with 2hG, suggesting potential differences in postprandial glucose metabolism inside and outside of pregnancy. [ABSTRACT FROM AUTHOR]

Objective: Reliable biomarkers associated with aggressiveness of non-functioning gonadotroph adenomas (GAs) are lacking. As the growth of tumor remnants is highly variable, molecular markers for growth potential prediction are necessary. We hypothesized that fast- and slow-growing GAs present different gene expression profiles and reliable biomarkers for tumor growth potential could be identified, focusing on the specific role of epithelial-mesenchymal transition (EMT). Design and methods: Eight GAs selected for RNA sequencing were equally divided into fast- and slow-growing group by the tumor volume doubling time (TVDT) median (27.75 months). Data were analyzed by tophat2, cufflinks and cummeRbund pipeline. 40 genes were selected for RT-qPCR validation in 20 GAs based on significance, fold-change and pathway analyses. The effect of silencing MTDH (metadherin) and EMCN (endomucin) on in vitro migration of human adenoma cells was evaluated. Results: 350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group, P-adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (--0.669

Objective: A proinflammatory imbalance in the tumor necrosis factor (TNF) system may contribute to the pathogenesis of schizophrenia (SCZ) and bipolar disorders (BDs) and related comorbidities. We investigated the relative distribution of TNF-related molecules in blood and dorsolateral prefrontal cortex (DLPFC) in these disorders. Method: We measured plasma levels of TNF, soluble TNF receptor 1 (sTNFR1), soluble TNF receptor 2 (sTNFR2), and a disintegrin and metalloprotease-17 (ADAM17) using enzyme immunoassays and calculated the TNF/sTNFRs ratio (TNF/sTNFR1+sTNFR2) in a sample of 816 SCZ and BD spectrum patients and 624 healthy controls (HCs). TNF, TNFRSF1A (TNFR1), TNFRSF1B (TNFR2), and ADAM17 mRNA levels were determined in whole blood, and postmortem DLPFC obtained from an independent cohort (n = 80 SCZ, n = 44 BD, and n = 86 HC). Results: In peripheral blood, we show increased TNF-related measures in patients compared to HC, with an increased TNF/sTNFRs ratio (p = 6.00 x 10-5), but decreased TNF mRNA expression (p = 1 x 10-4), with no differences between SCZ and BD. Whole blood ADAM17 mRNA expression was markedly higher in BD vs SCZ patients (p = 1.40 x 10-14) and vs HC (p = 1.22 x 10-8). In postmortem DLPFC, we found no significant differences in mRNA expression of TNF pathway genes between any groups. Conclusions: SCZ and BD patients have increased plasma TNF pathway markers without corresponding increase in blood cell gene expression. ADAM17 expression in leukocytes is markedly different between the two disorders, while alterations in TNF-related gene expression in DLPFC are uncertain. Further studies are necessary to elucidate the aberrant regulation of the TNF pathway in severe mental disorders. [ABSTRACT FROM AUTHOR]

Context: Glucose intolerance in pregnancy predicts an increased risk of future type 2 diabetes. Objective: The aim of the study was to evaluate glucose metabolism in women with and without gestational diabetes mellitus (GDM) at 5 years follow-up and identify risk factors associated with disturbed glucose metabolism post-partum. Design: This follow-up study included 300 consecutively enrolled women from a previous population-based cohort study. The participants underwent oral glucose tolerance test under pregnancy and in the follow-up study, in addition to dual-energy X-ray absorptiometry in the follow-up study. Results: Fifty-two women (17.7%) were found to have GDM in pregnancy with an odds ratio of 4.8 developing prediabetes 5 years later. b-cell function, but not insulin resistance or sensitivity, was reduced in the follow-up study after adjusting for known risk factors. Furthermore, visceral fat content at follow-up was increased in GDM women compared to non-GDM women, and the b-cell function declined with increasing visceral fat in both groups but was more pronounced in the women with previous GDM. Conclusions: Women with GDM are at increased risk of developing prediabetes and have a decreased b-cell function 5 years post-partum that is associated with increased visceral fat mass. [ABSTRACT FROM AUTHOR]

Context: During pregnancy, changes occur in the maternal calcium homeostasis to fulfill fetal demand. We hypothesized that the fibroblast growth factor 23 (FGF23) system and Wnt signaling pathway are important for normal skeletal development in the offspring. Aims: Circulating α-klotho, FGF23, sclerostin, and 25-hydroxyvitamin D (25(OH)D) at the fetal and maternal sides of the placenta were measured to investigate associations with newborn bone mass independent of maternal BMI, calcium and phosphate levels, placental weight, and birth weight. Methods: In a prospective cohort of healthy pregnant women, the total body bone mineral content (BMC) in 202 newborns was measured by dual-energy X-ray absorptiometry. Maternal circulating levels of the biomarkers were measured at gestational weeks 30-32 and in umbilical cord plasma (UCP) at birth. Results: Mean a-klotho and sclerostin concentrations in the UCP were significantly higher than maternal levels (3004 vs 1077 pg/ml; P<0.001 and 629 vs 346 pg/ml; P<0.001 respectively), and mean 25(OH)D was lower (31 vs 45 nmol/l; P<0.001). The UCP and maternal FGF23 levels were similar. No significant effects of maternal biomarkers on BMC were found in regression analyses. Among UCP biomarkers, only UCP sclerostin was significantly associated with BMC in univariate analyses, and the effect remained significant after adjustment for birth weight and other confounders. Conclusions: We found that UCP sclerostin levels, birth weight, and placental weight were significant predictors of neonatal BMC but found no evidence for a main role of maternal levels of α-klotho, FGF23, sclerostin, or 25(OH)D nor of UCP levels of a-klotho, FGF23, or 25(OH)D. [ABSTRACT FROM AUTHOR]

Objective: Patients with endogenous Cushing's Syndrome (CS), as long-time treated patients with exogenous glucocorticoids (GCs), have severe systemic manifestations including secondary osteoporosis and low-energy fractures. The aim of the present study was to investigate the functional role of TXNIP in bone with focus on osteoblast (OB) differentiation and OB-mediated osteoclast activity and function in vitro. Design and methods: Nine bone biopsies from CS before and after surgical treatment were screened for expressional candidate genes. Microarray analyses revealed that the gene encoding TXNIP ranked among the most upregulated genes. Subsequent in vitro and in vivo studies were performed. Results: We found that TXNIP gene in bone is downregulated in CS following surgical treatment. Furthermore, our in vivo data indicate novel associations between thioredoxin and TXNIP. Our in vitro studies showed that silencing TXNIP in OBs was followed by increased differentiation and expression and secretion of osteocalcin as well as enhanced activity of alkaline phosphatase. Moreover, treating osteoclasts with silenced TXNIP OB media showed an increased osteoclast activity. Conclusions: TXNIP expression in bone is highly regulated during the treatment of active CS, and by GC in bone cells in vitro. Our data indicate that TXNIP may mediate some of the detrimental effects of GC on OB function as well as modulate OB-mediated osteoclastogenesis by regulating the OPG/RANKL ratio. [ABSTRACT FROM AUTHOR]