Background: More accurate diagnosis of mucinous cysts will reduce the risk of unnecessary pancreatic surgery. Carcinoembryonic antigen (CEA) and glucose in pancreatic cyst fluid (PCF) can... Show moreBackground: More accurate diagnosis of mucinous cysts will reduce the risk of unnecessary pancreatic surgery. Carcinoembryonic antigen (CEA) and glucose in pancreatic cyst fluid (PCF) can differentiate mucinous from non-mucinous pancreatic cystic neoplasms (PCN). The current study assessed the value of combined CEA and glucose testing in PCF. Methods: Cross-sectional validation study including prospectively collected PCF from patients undergoing endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) and pancreatic surgery. We performed laboratory measurements for CEA and glucose and measured glucose levels by a hand glucometer. Primary outcome was diagnostic accuracy evaluated by receiver operator curves (ROC), sensitivity, specificity, positive, and negative predictive value (PPV, NPV). Results: Overall, PCF was collected from 63 patients, including 33 (52%) with mucinous and 30 (48%) with non-mucinous PCN. Histopathology (n = 36; 57%), cytopathology (n = 2; 3%), or clinical and/or radiological diagnosis (n = 25; 40%) was used as reference standard. Combined CEA (cut-off >= 192 ng/ml) and laboratory glucose testing (cut-off < 50 mg/dL) reached 92% specificity and 48% sensitivity, whereas either positive CEA (cut-off >= 20 ng/ml) or glucose testing (cut-off < 50 mg/ dL) showed 97% sensitivity and 50% specificity. Sensitivity and specificity were 80% and 68% for CEA >= 20 ng/mL versus 50% and 93% for CEA >= 192 ng/mL (the conventional cut-off level). Laboratory and glucometer glucose both reached 100% sensitivity and 60% and 45% specificity, respectively. None of the biomarkers and cut-offs reached a PPV exceeding 90%, whereas both glucose measurements had a NPV of 100% (i.e., high glucose excludes a mucinous cyst). Conclusion: Combined CEA and glucose testing in PCF reached high specificity and sensitivity for differentiating mucinous from non-mucinous PCN. Glucose testing, whether alone or combined with the new CEA cut-off (>= 20 ng/mL), reached > 95% sensitivity for mucinous cysts, whereas only glucose reached a NPV > 95%. Show less
Objective: Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 2013dihydrocorticosterone (2013-DHB), is upregulated in... Show moreObjective: Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 2013dihydrocorticosterone (2013-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states. Methods: The actions of 2013-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding. Results: 2013-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 2013-DHB and absent in female mice with higher baseline adipose 2013-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding. Conclusions: Carbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice. (c) 2021 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Several studies during the past decade have shown that patients with venous thrombosis have an increased risk of subsequent arterial thrombosis, thus suggesting a link between the two diseases. The... Show moreSeveral studies during the past decade have shown that patients with venous thrombosis have an increased risk of subsequent arterial thrombosis, thus suggesting a link between the two diseases. The aim of this thesis was to investigate the associations of traditional cardiometabolic risk factors with risk of a first and recurrent venous thrombosis. We showed that levels of major lipids, i.e. total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides, were not associated with a first venous thrombosis. In contrast, low levels of apolipoproteins B and A1 were associated with an increased risk of a first event. Regarding recurrence, tests for lipid levels, glucose levels and hematologic variables did not identify patients at an increased risk of recurrent venous thrombosis, and these tests should not be done for this indication nor influence decisions on duration of anticoagulant treatment. In this thesis, we further searched for associations between lipids and hemostatic factors, and found that levels of vitamin K-dependent factors (VKDFs), including factor IX, were associated with triglyceride levels. We hypothesized that this association could be explained by common mechanisms, regulating levels of both VKDFs and triglycerides. Show less
Bruin, C.D.E. de; Lugt, N.M. van der; Visser, R.; Oostdijk, W.; Zwet, E.W. van; Pas, A.B. te; Lopriore, E. 2016
Although mortality in old age has significantly decreased over the last fifty years in the developed world, there still remains a large inter-individual variability in ageing trajectories,... Show more Although mortality in old age has significantly decreased over the last fifty years in the developed world, there still remains a large inter-individual variability in ageing trajectories, morbidity and mortality. In the three parts of this thesis, we examined three interacting systems that have been identified as contributing to a slower pace of ageing, namely glucose/insulin metabolism (part I), the thyroid axis (part II), and the autonomic nervous system (part III). We found that familial longevity is associated with a stronger association of insulin parameters with microstructural brain parameters, and by higher TSH secretion, in the absence of differences in basal energy metabolism or differences in heart rate and its variability. Using specialized MRI techniques, we showed that subtle changes in microstructural brain parenchymal homogeneity in relation to insulin can be detected, even in brain tissue that appears normal on conventional MR imaging sequences. Insulin (rather than glucose), seemed to be a stronger indicator of micro- structural brain integrity in normo-glycemic older adults. Furthermore, intranasal application of insulin improved brain perfusion in parietal and occipital gray matter and in the thalamus of older adults. These results deepen our understanding of the physiological mechanisms and processes that underlie the ageing process. Show less
Garessus, E.D.G.; Mutsert, R. de; Visser, A.W.; Rosendaal, F.R.; Kloppenburg, M. 2016
Conclusion: An impaired glucose metabolism does not seem be related to OA. In men, an association was observed for fasting glucose concentrations and hand OA. Future studies should investigate the... Show moreConclusion: An impaired glucose metabolism does not seem be related to OA. In men, an association was observed for fasting glucose concentrations and hand OA. Future studies should investigate the presence of sex differences in the pathogenesis of hand OA. (C) 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
This thesis aims to describe the role of glucose metabolism in human longevity and to translate the results to an intervention aimed at improving health in older age in the general population. In... Show moreThis thesis aims to describe the role of glucose metabolism in human longevity and to translate the results to an intervention aimed at improving health in older age in the general population. In the first part, we describe evidence for enhanced glucose metabolism in long-lived families. Middle-aged individuals predisposed to longevity were characterized by enhande insulin action at the level of the skeletal muscle, lower accumulation of intramyocellular lipids and lower nocturnal glucose levels. These results have provided the biological basis upon which health-promoting intervention in older age may be funded. In the second part, we have shonw that an internet-based intervention is effective at increasing physical activity and improving health in an older population. Furthermore, increasing total daily physical activity in sedentary elderly was shown to lead to better metabolic health. Show less
De activatie van zowel witte bloedcellen als complement systeem (betrokken bij het immuunsysteem) zijn geassocieerd met atherosclerose (slagaderverkalking). Het proefschrift bestaat uit drie delen;... Show moreDe activatie van zowel witte bloedcellen als complement systeem (betrokken bij het immuunsysteem) zijn geassocieerd met atherosclerose (slagaderverkalking). Het proefschrift bestaat uit drie delen; In deel I laten wij in 3 hoofdstukken zien dat vetten belangrijker zijn dan glucose voor de activatie van de witte bloedcellen en dus meer in staat zijn om een ontstekingsfenomeen op gang te brengen die leidt tot slagaderverkalking. Verder laten wij zien dat pati_nten met familiair verhoogd cholesterol (FH) en familiair verhoogd cholesterol en verhoogde voedingsvetten (triglyceriden) (FGH) na glucose-belasting een blijvende witte bloedcelactivatie hebben in tegenstelling tot gezonde vrijwilligers. Tenslotte werd aangetoond dat het structurele eiwit van de partikels waarin voedingsvetten vanuit de darmen worden vervoerd (apoB48) geassocieerd is met intima media dikte (een marker voor slagaderverkalking) In deel II associ_ren wij in 3 hoofstukken witte bloedcelactivatie met slagaderverkalking. Zo werd bijvoorbeeld aangetoond dat er in de kransslagaders met slagaderverkalking een hogere witte bloedcelactivatiestatus is dan in andere kransslagaders en bloedvaten zonder slagaderverkalking. Verder is de activatie van monocyten (een subgroep van witte bloedcellen) een voorspeller voor toekomstige hart- en vaatziekten. In deel III zijn ook 3 hoofdstukken beschreven met daarin de rol van mannose bindend lectine (MBL) die een van de routes is van complementactivatie (betrokken bij immuniteit; opruimen van lichaamsvreemde stoffen zoals bacteri_n). In hoofdstuk 1 werd beschreven dat mensen die lage MBL-waarden hebben, een minder effici_ntere vetstofwisseling hebben dan mensen met voldoende MBL-waarden. Echter, als we puur naar slagaderverkalking kijken, zien we dat MBL geen invloed heeft op de progressie van krasslagaderverkalking bij mensen met pre-existent krasslagaderverkalking. Show less
