Publications by authors named "Tove Lekva"

56 Publications

Secreted Wnt antagonists in scrub typhus.

PLoS Negl Trop Dis 2021 Apr 29;15(4):e0009185. Epub 2021 Apr 29.

Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.

Background: The mechanisms that control local and systemic inflammation in scrub typhus have only been partially elucidated. The wingless (Wnt) signaling pathways are emerging as important regulators of inflammation and infection, but have not been investigated in scrub typhus.

Methodology/principal Findings: Plasma levels of secreted Wnt antagonists (i.e. DKK-1, sFRP-3, WIF-1 and SOST) were analyzed in patients with scrub typhus (n = 129), patients with similar febrile illness without O. tsutsugamushi infection (n = 31), febrile infectious disease controls, and in healthy controls (n = 31) from the same area of South India, and were correlated to markers of inflammation, immune and endothelial cell activation as well as for their association with organ specific dysfunction and mortality in these patients. We found i) Levels of SOST and in particular sFRP-3 and WIF-1 were markedly increased and DKK-1 decreased in scrub typhus patients at admission to the hospital compared to healthy controls. ii) In recovering scrub typhus patients, SOST, sFRP-3 and WIF-1 decreased and DKK-1 increased. iii) SOST was positively correlated with markers of monocyte/macrophage and endothelial/vascular activation as well as with renal dysfunction and poor outcome iv) Finally, regulation of Wnt pathways by O. tsutsugamushi in vitro in monocytes and ex vivo in mononuclear cells isolated from patients with scrub typhus, as evaluated by gene expression studies available in public repositories, revealed markedly attenuated canonical Wnt signaling.

Conclusions/significance: Our findings suggest that scrub typhus is characterized by attenuated Wnt signaling possibly involving dysregulated levels of several secreted pathway antagonists. The secreted Wnt antagonist SOST was strongly associated with renal dysfunction and poor prognosis in these patients.
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http://dx.doi.org/10.1371/journal.pntd.0009185DOI Listing
April 2021

Low CETP activity and unique composition of large VLDL and small HDL in women giving birth to small-for-gestational age infants.

Sci Rep 2021 Mar 18;11(1):6213. Epub 2021 Mar 18.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Cholesteryl ester transfer protein (CETP) regulates high density lipoproteins (HDL)-cholesterol (C) and HDL-C is essential for fetal development. We hypothesized that women giving birth to large-for-gestational-age (LGA) and small-for-gestational age (SGA) infants differed in longitudinal changes in lipoproteins, CETP activity and HDL-C and that placentas from women with higher or lower circulating HDL-C displayed differential expression of mRNAs involved in cholesterol/nutrient transport, insulin signaling, inflammation/ extracellular matrix (ECM) remodeling. Circulating lipids and CETP activity was measured during pregnancy, NMR lipidomics in late pregnancy, and associations with LGA and SGA infants investigated. RNA sequencing was performed in 28 placentas according to higher and lower maternal HDL-C levels. Lipidomics revealed high triglycerides in large VLDL and lipids/cholesterol/cholesteryl esters in small HDL in women giving birth to SGA infants. Placentas from women with higher HDL-C had decreased levels of CETP expression which was associated with mRNAs involved in cholesterol/nutrient transport, insulin signaling and inflammation/ECM remodeling. Both placental and circulating CETP levels were associated with growth of the fetus. Low circulating CETP activity at 36-38 weeks was associated with giving birth to SGA infants. Our findings suggest a link between increased maternal HDL-C levels, low CETP levels both in circulation and placenta, and SGA infants.
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http://dx.doi.org/10.1038/s41598-021-85777-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973737PMC
March 2021

Pregnancy and postpartum levels of circulating maternal sHLA-G in preeclampsia.

J Reprod Immunol 2021 02 17;143:103249. Epub 2020 Nov 17.

Division of Obstetrics and Gynaecology, Oslo University Hospital, Norway; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.

Preeclampsia is a leading cause of maternal and offspring mortality and morbidity, and predicts increased future cardiovascular disease risk. Placental dysfunction and immune system dysregulation are likely key pathophysiological factors. Soluble human leukocyte antigen G (sHLA-G) may dampen the specific immune response towards placental trophoblasts. Previous studies have shown low sHLA-G levels in preeclampsia, but postpartum, levels are unknown. Furthermore, the relationship between sHLA-G and sFlt-1 and PlGF, placental function markers, is unknown. We hypothesized that low maternal sHLA-G during pregnancy would be associated with placental dysfunction, including preeclampsia, gestational hypertension, and dysregulated sFlt-1 and PlGF, and that sHLA-G would remain decreased following preeclampsia. We included 316 pregnant women: 58 with early-onset preeclampsia (<34 weeks' gestation), 81 with late-onset preeclampsia (≥34 weeks' gestation), 25 with gestational hypertension, and 152 normotensive controls. Postpartum (1 or 3 years), we included 321 women: 29 with early-onset preeclampsia, 98 with late-onset preeclampsia, 57 with gestational hypertension, and 137 who were normotensive during their index pregnancies. In pregnancy, plasma sHLA-G was significantly lower both in the early- and late-onset preeclampsia groups compared to controls. In women with preeclampsia or gestational hypertension, sHLA-G was inversely correlated with serum sFlt-1. Postpartum, plasma sHLA-G levels were significantly higher in women who had had early-onset preeclampsia compared to controls. Our results support that sHLA-G may be important for placental function. Unexpectedly, sHLA-G was elevated up to 3 years after early-onset preeclampsia, suggesting an excessively activated immune system following this severe preeclampsia form, potentially contributing to future cardiovascular disease risk.
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http://dx.doi.org/10.1016/j.jri.2020.103249DOI Listing
February 2021

Distinct patterns of soluble leukocyte activation markers are associated with etiology and outcomes in precapillary pulmonary hypertension.

Sci Rep 2020 10 29;10(1):18540. Epub 2020 Oct 29.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, 0027, Oslo, Norway.

Activation of inflammatory processes has been identified as a major driver of pulmonary vascular remodeling that contributes to the development of precapillary pulmonary hypertension (PH). We hypothesized that circulating markers of leukocyte activation, reflecting monocytes/macrophages (sCD163, sCD14), T-cells (sCD25) and neutrophils (myeloperoxidase [MPO], neutrophil gelatinase-associated lipocalin [NGAL]) activity, could give prognostic information in precapillary PH. Circulating markers of leucocyte activation, sCD163, sCD14, sCD25, MPO and NGAL were measured by enzyme immunoassays in plasma from patients with idiopathic PAH (IPAH; n = 30); patients with PAH related to associated conditions (APAH; n = 44) and patients with chronic thromboembolic PH (CTEPH) (n = 32), and compared with 23 healthy controls. Markers of leucocyte activation were elevated in precapillary PH with particularly high levels in APAH. The elevated levels of monocyte/macrophage marker sCD163 was independently associated with poor long-term prognosis in the group as a whole, and elevated levels of sCD25 was associated with poor prognosis in APAH, while elevated levels of sCD163 and NGAL was associated with poor prognosis in IPAH and CTEPH. Our data show leucocyte activation in precapillary PH with different profiles and impact on prognosis according to etiology. The association of sCD163 with poor outcome in fully adjusted model may be of particular interest.
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http://dx.doi.org/10.1038/s41598-020-75654-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596076PMC
October 2020

Distinct Pattern of Endoplasmic Reticulum Protein Processing and Extracellular Matrix Proteins in Functioning and Silent Corticotroph Pituitary Adenomas.

Cancers (Basel) 2020 Oct 14;12(10). Epub 2020 Oct 14.

Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital (OUS), 0424 Oslo, Norway.

Functioning (FCA) and silent corticotroph (SCA) pituitary adenomas act differently from a clinical perspective, despite both subtypes showing positive TBX19 (TPIT) and/or adrenocorticotropic hormone (ACTH) staining by immunohistochemistry. They are challenging to treat, the former due to functional ACTH production and consequently hypercortisolemia, and the latter due to invasive and recurrent behavior. Moreover, the molecular mechanisms behind their distinct behavior are not clear. We investigated global transcriptome and proteome changes in order to identify signaling pathways that can explain FCA and SCA differences (e.g., hormone production vs. aggressive growth). In the transcriptomic study, cluster analyses of differentially expressed genes revealed two distinct groups in accordance with clinical and histological classification. However, in the proteomic study, a greater degree of heterogeneity within the SCA group was found. Genes and proteins related to protein synthesis and vesicular transport were expressed by both adenoma groups, although different types and a distinct pattern of collagen/extracellular matrix proteins were presented by each group. Moreover, several genes related to endoplasmic reticulum protein processing were overexpressed in the FCA group. Together, our findings shed light on the different repertoires of activated signaling pathways in corticotroph adenomas, namely, the increased protein processing capacity of FCA and a specific pattern of adhesion molecules that may play a role in the aggressiveness of SCA.
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http://dx.doi.org/10.3390/cancers12102980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650558PMC
October 2020

YKL-40 (Chitinase-3-Like Protein 1) Serum Levels in Aortic Stenosis.

Circ Heart Fail 2020 10 23;13(10):e006643. Epub 2020 Sep 23.

Research Institute of Internal Medicine (F.A., A.A., A.E.M., T.L., S.H., B.H., A.V.F., L.-E.V., S.N., T.R., P.A., T.U.), Institute of Basic Medical Sciences, University of Oslo, Norway.

Background: Identification of novel biomarkers could provide prognostic information and improve risk stratification in patients with aortic stenosis (AS). YKL-40 (chitinase-3-like protein 1), a protein involved in atherogenesis, is upregulated in human calcific aortic valves. We hypothesized that circulating YKL-40 would be elevated and associated with the degree of AS severity and outcome in patients with symptomatic AS.

Methods: Plasma YKL-40 was analyzed in 2 AS populations, one severe AS (n=572) with outcome measures and one with mixed severity (n=67). YKL-40 expression in calcified valves and in an experimental pressure overload model was assessed.

Results: We found (1) patients with AS had upregulated circulating YKL-40 compared with healthy controls (median 109 versus 34 ng/mL, <0.001), but levels were not related to the degree of AS severity. (2) High YKL-40 levels (quartile 4) were associated with long-term (median follow-up 4.7 years) all-cause mortality (adjusted hazard ratio, 1.93 [95% CI, 1.37-2.73], <0.001). (3) YKL-40 protein expression in human calcific valves co-localized with its putative receptor IL-13rα2 in close proximity to valve interstitial cells. (4) Myocardial YKL-40 increased in experimental pressure overload (6-fold in decompensated versus sham mice).

Conclusions: YKL-40 levels were elevated in AS and associated with mortality but not with other metrics of disease severity including the degree of AS severity. Despite scientific rationale for its role in AS, the clinical utility of circulating YKL-40 as a biomarker is limited. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794832.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006643DOI Listing
October 2020

Reduced levels of circulating adhesion molecules in adolescents with early-onset psychosis.

NPJ Schizophr 2020 Aug 18;6(1):20. Epub 2020 Aug 18.

NORMENT Center of Excellence, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.

It is suggested that neurodevelopmental abnormalities are involved in the disease mechanisms of psychotic disorders. Although cellular adhesion molecules (CAMs) participate in neurodevelopment, modulate blood-brain barrier permeability, and facilitate leukocyte migration, findings concerning their systemic levels in adults with psychosis are inconsistent. We examined plasma levels and mRNA expression in peripheral blood mononuclear cells (PBMCs) of selected CAMs in adolescents with early-onset psychosis (EOP) aged 12-18 years (n = 37) and age-matched healthy controls (HC) (n = 68). EOP patients exhibited significantly lower circulating levels of soluble platelet selectin (~-22%) and soluble vascular cell adhesion molecule-1 (~-14%) than HC. We found no significant associations with symptom severity. PSEL mRNA expression was increased in PBMCs of patients and significantly negatively correlated to duration of illness. These findings suggest a role for CAMs in the pathophysiology of psychotic disorders.
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http://dx.doi.org/10.1038/s41537-020-00112-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434772PMC
August 2020

Changes in maternal blood glucose and lipid concentrations during pregnancy differ by maternal body mass index and are related to birthweight: A prospective, longitudinal study of healthy pregnancies.

PLoS One 2020 23;15(6):e0232749. Epub 2020 Jun 23.

Department of Clinical Medicine, University of Oslo, Oslo, Norway.

Background: Maternal obesity is increasing worldwide but the consequences for maternal physiology and fetal growth are not fully understood.

Objective: To study whether changes in glucose and lipid metabolism during pregnancy differ between women with normal weight and overweight/obesity, and investigate which of these metabolic factors are associated with birthweight.

Design: Prospective, longitudinal study.

Setting: Department of Obstetrics, Oslo University Hospital, Rikshospitalet.

Population: 1031 healthy pregnant women with singleton pregnancies.

Methods: Blood samples from early and late pregnancy were analyzed for fasting glucose, insulin and lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol and triglycerides). Associations between metabolic factors and birthweight (z-scores) were explored by linear regression models. Main Outcome Measures: Group-dependent longitudinal changes in glucose and lipids and their association with birthweight (z-scores).

Results: Compared to women with normal weight (BMI < 25), women with overweight (BMI 25-29.9) and obesity (BMI > 30) had significantly higher fasting glucose (4.54, 4.68 and 4.84 mmol/l), insulin (23, 33 and 50 pmol/l), total cholesterol (4.85, 4.99 and 5.14 mmol/l), LDL-C (2.49, 2.66 and 2.88 mmol/l) and triglycerides (1.10, 1.28 and 1.57 mmol/l), but lower HDL-C (1.86, 1.75 and 1.55 mmol/l). BMI (B 0.05, 95% CI 0.03-0.06, p<0.001), gestational weight gain (GWG) (B 0.06, 0.05-0.08, p<0.001) and an increase in fasting glucose (B 0.30, 0.16-0.43, p<0.001) were positively associated with birthweight, whereas a decrease in HDL-C (B -0.72, -0.96- -0.53, p<0.001) had a negative association with birthweight.

Conclusions: Overweight/obesity was associated with an unfavorable metabolic profile in early pregnancy which was associated with increased birthweight. However, modifiable factors like gestational weight gain and an increase in fasting glucose were identified and can be targeted for interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232749PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310681PMC
August 2020

Multiplex Analysis of Circulating Maternal Cardiovascular Biomarkers Comparing Preeclampsia Subtypes.

Hypertension 2020 06 27;75(6):1513-1522. Epub 2020 Apr 27.

From the Department of Obstetrics and Gynecology, Oslo University Hospital, Ullevål, Norway (T.L., M.S., K.M., A.C.S.).

Preeclampsia, a hypertensive pregnancy disorder, links to increased long-term maternal cardiovascular disease (CVD). The risk is further increased with early-onset preeclampsia (EPE) and delivery of a growth-restricted child. We hypothesized that circulating biomarkers associated with CVD risk differed between preeclampsia subtypes and controls. We compared EPE; n=37, delivery
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14580DOI Listing
June 2020

Elevated levels of the secreted wingless agonist R-spondin 3 in preeclamptic pregnancies.

J Hypertens 2020 07;38(7):1347-1354

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet.

Objective: Preeclampsia is a syndrome characterized by hypertension and poor placental development. The developmental wingless (Wnt) pathway plays an important role in placental development and we hypothesized that Wnt signaling would be dysregulated in preeclampsia.

Methods: To elucidate aberrations in the Wnt signaling pathway we conducted a pathway analysis on placental mRNA in late-onset preeclampsia and normal pregnancy from the STORK study [n = 10 in each group, RNA sequencing (RNAseq)] to identify differentially expressed genes. In addition, we compared circulating levels of secreted Wnt agonists and antagonists at term pregnancy and 6 months postpartum from an acute preeclampsia study (preeclampsia n = 34, normal pregnancy n = 61).

Results: We found circulating and placental mRNA levels of the secreted Wnt agonist R-spondin 3 (RSPO3) at term elevated in preeclampsia. Increased plasma RSPO3 was associated with high mean arterial pressure. Further, pathway analysis of placental tissue revealed elevated mRNA levels of upstream ligands WNT6 and WNT10A and frizzled receptors 2 and 4 in preeclampsia and downstream activation of the noncanonical Ca/NFAT pathway. Finally, plasma dickkopf 3 was decreased in preeclampsia 6 months postpartum.

Conclusion: We identify a potential role for RSPO3 and activation of noncanonical Wnt signaling in preeclampsia.
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http://dx.doi.org/10.1097/HJH.0000000000002362DOI Listing
July 2020

Hip Structure Analyses in Acromegaly: Decrease of Cortical Bone Thickness After Treatment: A Longitudinal Cohort Study.

JBMR Plus 2019 Dec 23;3(12):e10240. Epub 2019 Oct 23.

Section of Specialized Endocrinology Oslo University Hospital Oslo Norway.

Long-standing growth hormone (GH) excess causes the skeletal clinical signs of acromegaly with typical changes in bone geometry, including increased cortical bone thickness (CBT). However, a high prevalence and incidence of vertebral fractures has been reported. The aim of this study was to assess the course of cortical bone dimensions in the hip by comparing patients with acromegaly and clinically nonfunctioning pituitary adenomas (NFPAs) at baseline and 1 year after pituitary surgery (1-year PO) in a longitudinal cohort study. DXA was performed in patients with acromegaly ( = 56) and NFPA ( = 47). CBT in the femoral neck (CBTneck), calcar (CBTcalcar), and shaft (CBTshaft) were determined by hip structural analysis (HSA). CBT at baseline and the change to 1-year PO were compared. Test results were adjusted for differences in gender distribution, age, and gonadal status. Cortical thickness analyses showed higher values [mm] at baseline in patients with acromegaly compared with NFPA: CBTneck median [25th; 75th] 6.2 [4.7; 8.0] versus 5.1 [4.1; 6.4] ( = 0.006), CBTcalcar 4.8 [4.2, 5.7] versus 4.0 [3.2, 4.5] ( < 0.001), CBTshaft 6.2 [5.1, 7.2] versus 5.2 [4.6, 6.0], ( = 0.003). In acromegaly, GH was correlated with CBTneck ( = 0.31, = 0.020), whereas IGF-1 was correlated with CBTcalcar ( = 0.39, = 0.003) at baseline. In acromegaly, CBTneck decreased by 11.2%, = 0.002 during follow-up. Finally, the decrease in CBTneck and CBTcalcar in acromegaly was significant compared with NFPA ( = 0.023 and = 0.017, respectively). Previous observations of increased CBT in acromegaly were confirmed with DXA-derived HSA in a large, well-defined cohort. The decline in CBT in acromegaly could contribute to the increased fracture risk in acromegaly despite increased bone dimensions and disease control. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894724PMC
December 2019

Increased interleukin 18 activity in adolescents with early-onset psychosis is associated with cortisol and depressive symptoms.

Psychoneuroendocrinology 2020 02 14;112:104513. Epub 2019 Nov 14.

Division of Mental Health and Addiction, Department of Psychiatric Research and Development, Oslo University Hospital, Oslo, Norway; Child and Adolescent Psychiatry Unit, Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Norway.

Objective: Evidence indicates that the pathophysiology of adult psychosis involves immune dysregulation, but its associations with stress are often not considered. The inflammatory cytokine interleukin (IL)-18, which is elevated in adult schizophrenia, is suggested to be sensitive to stress. We compared the associations of IL-18 with cortisol and clinical variables in adolescents with early-onset psychosis (EOP) aged 12-18 years and age-matched healthy controls (HC).

Method: We measured serum IL-18, IL-18 binding protein (IL-18BP), IL-18 receptor accessory protein (IL-18RAP), IL-18 receptor 1 (IL-18R1) and cortisol, and calculated the IL-18/IL-18BP ratio in patients (n = 31) and HC (n = 60). Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale and depressive symptoms by the Mood and Feelings Questionnaire-Child version (MFQ-C). Bivariate correlation analysis was used to explore relationships between IL-18/IL-18BP ratio and cortisol, depression and other clinical characteristics. Hierarchical multiple linear regression analysis was used to assess their individual contributions to the variance of the IL-18/IL-18BP ratio.

Results: Patients had significantly higher IL-18 levels and IL-18/IL-18BP ratios than HC, but similar IL-18BP, IL-18RAP and IL-18R1. Both cortisol (R change = 0.05) and the MFQ-C score (R change = 0.09) contributed significantly to the variance in IL-18/IL-18BP ratios after controlling for confounders.

Conclusion: We found increased IL-18 system activity in adolescents with EOP. Cortisol and depressive symptoms each contributed to the variance in the IL-18/IL-18BP ratio. Our findings support activation of inflammatory pathways in adolescent psychosis and suggest interactions between stress, inflammation and depressive symptoms in EOP.
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http://dx.doi.org/10.1016/j.psyneuen.2019.104513DOI Listing
February 2020

Elevated Cholesteryl Ester Transfer Protein Activity Early in Pregnancy Predicts Prediabetes 5 Years Later.

J Clin Endocrinol Metab 2020 03;105(3)

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Context: Cholesteryl ester transfer protein (CETP) regulates high-density lipoprotein (HDL) cholesterol levels and interaction between glucose, and HDL metabolism is central in the development of diabetes.

Objective: We hypothesized that CETP levels would be regulated in diabetic pregnancies. We tested the hypothesis by evaluating CETP activity measured multiple times during pregnancy and at 5 years' follow-up in a prospective cohort (STORK) and investigated its association with gestational diabetes mellitus (GDM) during pregnancy or development of prediabetes 5 years after pregnancy. We also evaluated the strongest correlation of CETP activity among measures of adipocity and glucose metabolism, lipoproteins, adipokines, and monocyte/macrophage activation markers.

Design: A population-based longitudinal cohort study was conducted from 2001 to 2013.

Setting: The study setting was Oslo University Hospital.

Patients Or Other Participants: A total of 300 women during pregnancy and at 5 years postpartum participated in this study.

Main Outcome Measures: CETP activity was measured at 14 to 16, 22 to 24, 30 to 32, and 36 to 38 weeks' gestation, and at 5 years' follow-up.

Results: We found higher CETP activity in pregnancy in women developing prediabetes but no association with GDM. CETP activity decreased throughout pregnancy and remained low at follow-up. High CETP activity was associated with sCD14 levels, in particular in women who developed prediabetes. These data show that enhanced CETP activity during pregnancy is associated with systemic indices of monocyte/macrophage activation, in particular in women who develop prediabetes later in life.

Conclusions: CETP activity during pregnancy identifies women at risk for later diabetes development.
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http://dx.doi.org/10.1210/clinem/dgz119DOI Listing
March 2020

Adipokines and macrophage markers during pregnancy-Possible role for sCD163 in prediction and progression of gestational diabetes mellitus.

Diabetes Metab Res Rev 2019 03 7;35(3):e3114. Epub 2019 Jan 7.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Aims: The risk of gestational diabetes mellitus (GDM) is increased in overweight and obese women potentially involving secreted mediators from adipose tissue. Our main aim was to evaluate if circulating adipokines and monocyte/macrophage markers were dysregulated in GDM and the influence body mass and indices of glucose metabolism had on this association. We further explored if early detection of these markers improved prediction of GDM and if they remained modified during long-term follow-up.

Materials And Methods: Population-based prospective cohort study in 273 pregnant women with markers measured four times during pregnancy and at 5-year follow-up.

Results: sCD163 was higher (25% at 14-16 weeks, P < 0.001) and adiponectin lower (-17% at 14-16 weeks, P < 0.01) early in pregnancy and at 5-year follow-up in GDM women, independent of BMI, and other GDM risk factors. Leptin, adiponectin, and chemerin were robustly associated with glucose metabolism throughout pregnancy while sCD163 was inversely associated with β-cell function early in pregnancy in women with increased BMI. Finally, the markers at 14 to 16 weeks displayed modest discriminatory properties with regard to prediction of GDM (AUC < 0.7). Using a combination of fasting glucose and sCD163, 53% of GDM could be identified when 25% of the population scored positive suggesting some merit in a multimarker approach.

Conclusions: sCD163 and adiponectin were dysregulated in GDM, independent of body mass. None of the adipokines or monocyte/macrophage activation markers displayed clinically useful properties alone for early detection of GDM. Activation of monocytes/macrophages may be an important event in the early development of GDM.
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http://dx.doi.org/10.1002/dmrr.3114DOI Listing
March 2019

Genetic determinants of glucose levels in pregnancy: genetic risk scores analysis and GWAS in the Norwegian STORK cohort.

Eur J Endocrinol 2018 Dec;179(6):363-372

Norwegian National Advisory Unit on Women's Health, Oslo, Norway.

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.
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http://dx.doi.org/10.1530/EJE-18-0478DOI Listing
December 2018

Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression.

Am J Transplant 2019 04 5;19(4):1050-1060. Epub 2018 Nov 5.

Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.

Cardiac allograft vasculopathy (CAV) causes heart failure after heart transplantation (HTx), but its pathogenesis is incompletely understood. Notch signaling, possibly modulated by everolimus (EVR), is essential for processes involved in CAV. We hypothesized that circulating Notch ligands would be dysregulated after HTx. We studied circulating delta-like Notch ligand 1 (DLL1) and periostin (POSTN) and CAV in de novo HTx recipients (n = 70) randomized to standard or EVR-based, calcineurin inhibitor-free immunosuppression and in maintenance HTx recipients (n = 41). Compared to healthy controls, plasma DLL1 and POSTN were elevated in de novo (P < .01; P < .001) and maintenance HTx recipients (P < .001; P < .01). Use of EVR was associated with a treatment effect for DLL1. For de novo HTx recipients, a change in DLL1 correlated with a change in CAV at 1 (P = .021) and 3 years (P = .005). In vitro, activation of T cells increased DLL1 secretion, attenuated by EVR. In vitro data suggest that also endothelial cells and vascular smooth muscle cells (VSMCs) could contribute to circulating DLL1. Immunostaining of myocardial specimens showed colocalization of DLL1 with T cells, endothelial cells, and VSMCs. Our findings suggest a role of DLL1 in CAV progression, and that the beneficial effect of EVR on CAV could reflect a suppressive effect on DLL1. Trial registration numbers-SCHEDULE trial: ClinicalTrials.gov NCT01266148; NOCTET trial: ClinicalTrials.gov NCT00377962.
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http://dx.doi.org/10.1111/ajt.15141DOI Listing
April 2019

Prediction of Gestational Diabetes Mellitus and Pre-diabetes 5 Years Postpartum using 75 g Oral Glucose Tolerance Test at 14-16 Weeks' Gestation.

Sci Rep 2018 09 6;8(1):13392. Epub 2018 Sep 6.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Early detection and treatment of women at risk for gestational diabetes mellitus (GDM) could improve perinatal and long-term outcomes in GDM women and their offspring. We explored if a 75 g oral glucose tolerance test (OGTT) at 14-16 weeks of gestation could identify women who will (1) develop GDM or give birth to large-for-gestational-age (LGA) babies in 1031 pregnant women from the STORK study using different diagnostic criteria (WHO1999, IADPSG2010, WHO2013, NORWAY2017) and (2) develop pre-diabetes 5 years postpartum focusing on first trimester β-cell function in a separate study of 300 women from the STORK cohort. The sensitivity of the 14-16 week OGTT to identify women who would develop GDM or have LGA babies was low, and we could not identify alternative cut-offs to exclude women not at risk or identify women that could benefit from early intervention. First trimester β-cell function was a stronger determinant than third trimester β-cell function of predicting maternal pre-diabetes. In conclusion, in our normal low-risk population, the 75 g OGTT at 14-16 weeks is insufficient to identify candidates for early treatment of GDM or identify women not likely to develop GDM or have LGA babies. First trimester β-cell function may predict pre-diabetes 5 years postpartum.
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http://dx.doi.org/10.1038/s41598-018-31614-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127333PMC
September 2018

Gene expression profiling of fast- and slow-growing non-functioning gonadotroph pituitary adenomas.

Eur J Endocrinol 2018 Mar 19;178(3):295-307. Epub 2017 Dec 19.

Section of Specialized EndocrinologyDepartment of Endocrinology.

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 (metadherin) and (endomucin) on migration of human adenoma cells was evaluated.

Results: 350 genes were significantly differentially expressed (282 genes upregulated and 68 downregulated in the fast group, -adjusted <0.05). Among 40 selected genes, 11 showed associations with TVDT (-0.669<<-0.46,  < 0.05). These were and six EMT-related genes ( and ). , but not , demonstrated involvement in cell migration and association with EMT markers.

Conclusions: Fast- and slow-growing GAs present different gene expression profiles, and genes related to EMT have higher expression in fast-growing tumors. In addition to , identified as an important contributor to aggressiveness, the other genes might represent markers for tumor growth potential and possible targets for drug therapy.
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http://dx.doi.org/10.1530/EJE-17-0702DOI Listing
March 2018

CXC chemokine ligand 16 is increased in gestational diabetes mellitus and preeclampsia and associated with lipoproteins in gestational diabetes mellitus at 5 years follow-up.

Diab Vasc Dis Res 2017 11 31;14(6):525-533. Epub 2017 Aug 31.

1 Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Background: Women with a history of gestational diabetes mellitus and preeclampsia are at increased risk of cardiovascular disease later in life, but the mechanism remains unclear. The aim of the study was to evaluate the association between CXC chemokine ligand 16 and indices of glucose metabolism, dyslipidemia and systemic inflammation in gestational diabetes mellitus and preeclampsia.

Methods: This sub-study of the population-based prospective cohort included 310 women. Oral glucose tolerance test was performed during pregnancy and 5 years later along with lipid analysis. CXC chemokine ligand 16 was measured in plasma (protein) and peripheral blood mononuclear cells (messenger RNA) during pregnancy and at follow-up.

Results: Circulating CXC chemokine ligand 16 was higher in gestational diabetes mellitus women early in pregnancy and at follow-up, while higher in preeclampsia women late in pregnancy compared to control women. Messenger RNA of CXC chemokine ligand 16 in peripheral blood mononuclear cells were lower in gestational diabetes mellitus and preeclampsia women compared to control women. Increased circulating CXC chemokine ligand 16 level was associated with a higher apolipoprotein B and low-density lipoprotein cholesterol in gestational diabetes mellitus women but not in normal pregnancy at follow-up.

Conclusion: Our study shows that women with gestational diabetes mellitus and preeclampsia had a dysregulated CXC chemokine ligand 16 during pregnancy, and in gestational diabetes mellitus, the increase in CXC chemokine ligand 16 early in pregnancy and after 5 years was strongly associated with their lipid profile.
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http://dx.doi.org/10.1177/1479164117728011DOI Listing
November 2017

The Notch Ligands DLL1 and Periostin Are Associated with Symptom Severity and Diastolic Function in Dilated Cardiomyopathy.

J Cardiovasc Transl Res 2017 Aug 4;10(4):401-410. Epub 2017 May 4.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

In dilated cardiomyopathy (DCM), adverse myocardial remodeling is essential, potentially involving Notch signaling. We hypothesized that secreted Notch ligands would be dysregulated in DCM. We measured plasma levels of the canonical Delta-like Notch ligand 1 (DLL1) and non-canonical Notch ligands Delta-like 1 homologue (DLK1) and periostin (POSN) in 102 DCM patients and 32 matched controls. Myocardial mRNA and protein levels of DLL1, DLK1, and POSN were measured in 25 explanted hearts. Our main findings were: (i) Circulating levels of DLL1 and POSN were higher in patients with severe DCM and correlated with the degree of diastolic dysfunction and (ii) right ventricular tissue expressions of DLL1, DLK1, and POSN were oppositely associated with cardiac function indices, as high DLL1 and DLK1 expression corresponded to more preserved and high POSN expression to more deteriorated cardiac function. DLL1, DLK1, and POSN are dysregulated in end-stage DCM, possibly mediating different effects on cardiac function.
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http://dx.doi.org/10.1007/s12265-017-9748-yDOI Listing
August 2017

Large Reduction in Adiponectin During Pregnancy Is Associated With Large-for-Gestational-Age Newborns.

J Clin Endocrinol Metab 2017 07;102(7):2552-2559

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, 0027 Oslo, Norway.

Context: Fetuses exposed to an obese intrauterine environment are more likely to be born large-for-gestational age (LGA) and are at increased risk of obesity in childhood and cardiovascular disease and/or type 2 diabetes mellitus as adults, but which factors that influence the intrauterine environment is less clear.

Objective: To investigate the association between circulating levels of leptin and adiponectin, measured multiple times during pregnancy, and birth weight and prevalence of LGA or small-for-gestational-age infants. The association between birth weight and messenger RNA (mRNA) expression of adiponectin receptors and genes involved in nutrient transport in the placenta was also investigated.

Design: Population-based prospective cohort [substudy of the STORK study (STORe barn og Komplikasjoner, translated as Large Babies and Complications)] from 2001 to 2008.

Setting: University hospital. Patients or other participants: 300 women.

Main Outcome Measures: Oral glucose tolerance test was performed twice along with adiponectin and leptin levels measured four times during pregnancy.

Results: Circulating adiponectin was lower in mothers who gave birth to LGA offspring or had fetuses with high intrauterine abdominal circumference late in pregnancy. Adiponectin decreased most from early to late pregnancy in mothers who gave birth to LGA offspring, and the decrease was an independent predictor of birth weight. Adiponectin receptor 2 and system A amino acid transporter mRNA expression in placentas was negatively correlated with birth weight and was lower in placentas from LGA infants.

Conclusions: Our findings suggest that maternal adiponectin may be an important predictor of fetal growth and birth weight, independent of body mass index and insulin resistance.
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http://dx.doi.org/10.1210/jc.2017-00289DOI Listing
July 2017

Wnt5a is elevated in heart failure and affects cardiac fibroblast function.

J Mol Med (Berl) 2017 07 30;95(7):767-777. Epub 2017 Mar 30.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet; Postboks 4950 Nydalen, 0424, Oslo, Norway.

Wnt signaling is dysregulated in heart failure (HF) and may promote cardiac hypertrophy, fibrosis, and inflammation. Blocking the Wnt ligand Wnt5a prevents HF in animal models. However, the role of Wnt5a in human HF and its functions in cardiac cells remain unclear. Here, we investigated Wnt5a regulation in HF patients and its effects on primary mouse and human cardiac fibroblasts. Serum Wnt5a was elevated in HF patients and associated with hemodynamic, neurohormonal, and clinical measures of disease severity. In failing human hearts, Wnt5a protein correlated with interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1. Wnt5a messenger RNA (mRNA) levels were markedly upregulated in failing myocardium and both mRNA and protein levels declined following left ventricular assist device therapy. In primary mouse and human cardiac fibroblasts, recombinant Wnt5a dose-dependently upregulated mRNA and protein release of IL-6 and TIMP-1. Wnt5a did not affect β-catenin levels, but activated extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Importantly, inhibition of ERK1/2 activation attenuated Wnt5a-induced release of IL-6 and TIMP-1. In conclusion, our results show that Wnt5a is elevated in the serum and myocardium of HF patients and is associated with measures of progressive HF. Wnt5a induces IL-6 and TIMP-1 in cardiac fibroblasts, which might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression.

Key Messages: • Wnt5a is elevated in serum and myocardium of HF patients and is associated with measures of progressive HF. • In cardiac fibroblasts, Wnt5a upregulates interleukin (IL)-6 and tissue inhibitor of metalloproteinase (TIMP)-1 through the ERK pathway. • Wnt5a-mediated effects might promote myocardial inflammation and fibrosis, and thereby contribute to HF progression.
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http://dx.doi.org/10.1007/s00109-017-1529-1DOI Listing
July 2017

Leptin and adiponectin as predictors of cardiovascular risk after gestational diabetes mellitus.

Cardiovasc Diabetol 2017 01 10;16(1). Epub 2017 Jan 10.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Background: Gestational diabetes mellitus (GDM) is a significant risk factor for cardiovascular disease (CVD) in later life, but the mechanism remains unclear. Adipokine imbalance in the presence of metabolic dysfunction may be a key event in promoting CVD. The aim of the study was to examine the relationships between GDM, cardiovascular risk, and plasma adiponectin, leptin and the leptin/adiponectin (L/A) ratio in pregnancy and at 5 years after the index pregnancy.

Methods: This population-based prospective cohort included 300 women who had an oral glucose tolerance test (OGTT) during pregnancy. Five years later, the OGTT was repeated along with dual-energy X-ray absorptiometry, lipid analysis, and pulse wave velocity analysis. Fasting adiponectin and leptin levels were measured four times during pregnancy and at follow-up.

Results: We found the L/A ratio higher in GDM women both during pregnancy and follow-up compared to non-GDM women. A high L/A ratio during pregnancy was associated with CV risk based on lipid ratios at follow-up, especially the TG/HDL-C ratio. Further, interaction analysis indicated that an increase in the L/A ratio of 1 unit was associated with a higher CV risk in GDM compared to normal pregnancy. Finally, low adiponectin levels independently predicted increased lipid ratios at follow-up.

Conclusions: Taken together, our findings suggest that high L/A ratio in pregnancy and in particularly in those with GDM are associated with an unfavorable CVD risk profile during follow-up. Future studies should investigate if a dysregulated leptin and adiponectin profile during pregnancy is associated with atherosclerotic disease during long-term follow-up.
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http://dx.doi.org/10.1186/s12933-016-0492-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5223461PMC
January 2017

A Study of TNF Pathway Activation in Schizophrenia and Bipolar Disorder in Plasma and Brain Tissue.

Schizophr Bull 2017 07;43(4):881-890

NORMENT, KG Jebsen Centre for Psychosis Research Building 49, Oslo University Hospital, Ullevål Kirkeveien 166, PO Box 4956 Nydalen 0424, Oslo, Norway.

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 × 10-5), but decreased TNF mRNA expression (p = 1 × 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 × 10-14) and vs HC (p = 1.22 × 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.
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http://dx.doi.org/10.1093/schbul/sbw183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5515106PMC
July 2017

Selection and validation of reliable reference genes for RT-qPCR analysis in a large cohort of pituitary adenomas.

Mol Cell Endocrinol 2016 12 22;437:183-189. Epub 2016 Aug 22.

Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Oslo, Norway; Research Institute for Internal Medicine, Oslo University Hospital, Oslo, Norway.

Background: Real-time reverse transcription quantitative PCR (RT-qPCR) has become the method of choice for quantification of gene expression changes. The most important limitations of RT-qPCR are inappropriate data normalization and inconsistent data analyses. Pituitary adenomas are common tumours, and the appropriate interpretation of increasingly published data within this field is prevented by the lack of a proper selection and validation of stably expressed reference genes.

Aim: To find and validate the optimal reference gene or gene combination for reliable RT-qPCR gene expression in both non-functioning (NFPA) and hormone secreting (GH and ACTH) pituitary adenomas.

Material And Methods: Thirty commonly used reference genes (PCR array reference gene panel, BioRad, Hercules, CA) were quantified by RT-qPCR in 24 pituitary adenomas (12 NFPA, 8 GH and 4 ACTH). The data was analysed using three programs: geNorm (Qbase+), Normfinder and BestKeeper having different algorithms to identify the most stable reference gene or combination of reference genes. Three reference genes ALAS1, PSMC4 and GAPDH, were selected for further validation in a larger cohort of 223 adenomas (141 NFPA, 63 GH and 19 ACTH).

Results: In all adenomas, ALAS1 and PSMC4 were the most stable reference genes as estimated by geNorm and Normfinder, whereas Bestkeeper ranked RPLP0 and ACTB as the two most stable out of 10 carefully selected genes. The best gene combination was PSMC4 and ALAS1 (geNorm) or PSMC4 and GAPDH (Normfinder). The validation experiment (geNorm) showed that the most stable gene combinations were ALAS1 and GAPDH in NFPA, and PSMC4 and GAPDH in hormone secreting adenomas.

Conclusions: Several of the reference genes expressed good stability yielding several candidate genes. PSMC4 and ALAS1 were overall the most stably expressed genes in pituitary adenoma merely differing in ranking order. PSMC4 and ALAS1 have so far not been reported as reference genes in pituitary adenomas. The various reference gene algorithms showed a mixed selection of top ranked genes, thus suggesting a need for an individualised and rational choice of reference genes.
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http://dx.doi.org/10.1016/j.mce.2016.08.030DOI Listing
December 2016

Gene expression in term placentas is regulated more by spinal or epidural anesthesia than by late-onset preeclampsia or gestational diabetes mellitus.

Sci Rep 2016 07 11;6:29715. Epub 2016 Jul 11.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Pre-eclampsia (PE) and gestational diabetes mellitus (GDM) are common complications of pregnancy, but the mechanisms underlying these disorders remain unclear. The aim was to identify the extent of altered gene expression in term placentas from pregnant women with late-onset PE and GDM compared to controls. RNAseq identified few significantly differentially regulated genes in placental biopsies between PE, GDM, or uncomplicated pregnancy (n = 10 each group). Five genes were altered in placentas from PE including 4 non-coding genes and Angiopoietin 2 (ANGPT2). No genes were significantly regulated by GDM. In contrast, many genes were significantly regulated by fetal, maternal and delivery-specific variables, particularly spinal and epidural anesthesia. We selected ANGPT2 and Chemokine (C-X-C motif) ligand 14 (CXCL14) to test with qPCR in a larger set of placentas (n = 475) and found no differences between the groups. However, regression analysis revealed a stronger association between placental ANGPT2 and CXCL14 mRNA expression and fetal, maternal and delivery-specific variables than diagnostic group. To conclude, the gene expression in term placentas are highly affected by fetal, maternal and delivery specific variables. Few regulated genes were found in late-onset PE and GDM placentas, which may suggest that these conditions could be more affected by maternal factors.
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http://dx.doi.org/10.1038/srep29715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942618PMC
July 2016

Impact of Systemic Inflammation on the Progression of Gestational Diabetes Mellitus.

Curr Diab Rep 2016 Apr;16(4):26

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Sognsvannsveien 20, 0027, Oslo, Norway.

With increasing rates of obesity and new diagnostic criteria for gestational diabetes mellitus (GDM), the overall prevalence of GDM is increasing worldwide. Women with GDM have an increased risk of maternal and fetal complications during pregnancy as well as long-term risks including higher prevalence of type 2 diabetes mellitus and cardiovascular disease. In recent years, the role of immune activation and inflammation in the pathogenesis of GDM has gained increasing attention. This monograph explores the current state of the literature as regards the expression of markers of inflammation in the maternal circulation, placenta, and adipose tissue of women with GDM.
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http://dx.doi.org/10.1007/s11892-016-0715-9DOI Listing
April 2016

Low circulating pentraxin 3 levels in pregnancy is associated with gestational diabetes and increased apoB/apoA ratio: a 5-year follow-up study.

Cardiovasc Diabetol 2016 Feb 3;15:23. Epub 2016 Feb 3.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Background: Gestational diabetes mellitus (GDM) is a significant risk factor for cardiovascular disease (CVD) in later life. Pentraxin 3 (PTX3) is an essential component of innate immunity and independently associated with the risk of developing vascular events. The aim of the study was to examine the relationships between GDM, cardiovascular risk, and plasma PTX3 in pregnancy and at 5 years after the index pregnancy.

Methods: This population-based prospective cohort included 300 women who had an oral glucose tolerance test (OGTT) during pregnancy. Five years later, the OGTT was repeated along with dual-energy x-ray absorptiometry, lipid analysis, and pulse wave velocity analysis. Fasting PTX3 levels were measured four times during pregnancy and at follow-up.

Results: PTX3 levels were lower early in pregnancy and at 5 years follow-up in women who developed GDM. PTX3 levels throughout pregnancy were associated with body mass index. Low PTX3 levels in early pregnancy were predictive of an increased apoB/apoA ratio at 5-year follow-up. PTX3 at 5-year follow-up was inversely correlated with multiple metabolic risk factors for CVD, including body composition, arterial stiffness, dyslipidemia and previous GDM.

Conclusions: Our results show that low plasma concentration of PTX3 in early pregnancy is associated with subsequent development of GDM and with an enhanced risk for CVD as estimated by an elevated apoB/apoA ratio at 5 years postpartum.
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http://dx.doi.org/10.1186/s12933-016-0345-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739426PMC
February 2016

Aortic Stiffness and Cardiovascular Risk in Women with Previous Gestational Diabetes Mellitus.

PLoS One 2015 26;10(8):e0136892. Epub 2015 Aug 26.

Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.

Gestational diabetes mellitus (GDM) is a significant risk factor for cardiovascular disease (CVD) in later life, but the mechanism remains unclear. The aim of the study was to investigate indices of glucose metabolism, dyslipidemia, and arterial stiffness (as measured by pulse wave velocity (PWV)), in women with and without a history of GDM, using both the old WHO and new IADPSG diagnostic criteria, at 5 years after the index pregnancy. Dyslipidemia and PWV were used as surrogate markers for CVD risk. The population-based prospective cohort included 300 women from the original STORK study. All participants had an oral glucose tolerance test (OGTT) during pregnancy. Five years later, the OGTT was repeated along with dual-energy x-ray absorptiometry, lipid analysis, and PWV analysis. Measurements were compared between those women who did and did not have GDM based on both the WHO and IADPSG criteria. We found that women with GDM based on the old WHO criteria had higher CVD risk at 5 years than those without GDM, with markedly elevated PWV and more severe dyslipidemia (higher triglycerides (TG)/HDL cholesterol ratio). After adjusting for known risk factors, the most important predictors for elevated PWV and TG/HDL-C ratio at 5-year follow-up were maternal age, BMI, GDM, systolic blood pressure, and indices of glucose metabolism in the index pregnancy. In conclusion, we found a higher risk for CVD, based on the surrogate markers PWV and TG/HDL-C ratio, at 5-year follow-up in women diagnosed with GDM in the index pregnancy when using the old WHO diagnostic criteria.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0136892PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550237PMC
May 2016

Alternative splicing of placental lactogen (CSH2) in somatotroph pituitary adenomas.

Neuro Endocrinol Lett 2015 ;36(2):136-42

Research Institute for Internal Medicine, Oslo University Hospital, Oslo, Norway.

Objectives: Somatotroph adenomas secrete supraphysiological amounts of GH, causing acromegaly. We have previously shown epithelial splicing regulator 1 (ESRP1) to play a role in epithelial mesenchymal transition (EMT) progression in these adenomas and account for poor treatment response. We evaluated if the mRNA levels of the GH/CSH gene cluster in somatotroph adenomas are associated with an epithelial phenotype and response to SA treatment.

Methods: We investigated the associations between ESRP1 and the growth hormone/chorionic somatomammotropin (GH/CSH) gene cluster by RNA sequencing (RNAseq). CSH2 isoform 3 mRNA was further evaluated in 65 somatotroph adenomas and associations with disease severity and treatment response.

Results: mRNA for all genes in the GH/CSH cluster were expressed, however, only chorionic somatomammotropin 2/placental lactogen 2 (CSH2) displayed an alternative splicing pattern. CSH2 isoform 3 was associated with a dense granulation pattern and an epithelial phenotype with high levels of ESRP1 and E-cadherin expression. Further, CSH2 isoform 3 was associated with reduced serum GH and IGF-I levels after somatostatin analog treatment.

Conclusions: Attenuated CSH2 isoform 3 was associated with mesenchymal phenotype and a blunted clinical response to somatostatin analog treatment in patients with acromegaly.
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September 2015