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Die Phyllosphäre
(2015)
Aminosäuren sind lebensnotwendige Moleküle für alle Organismen. Ihre Erkennung im Körper ermöglicht eine bedarfsgerechte Regulation ihrer Aufnahme und ihrer Verwertung. Welcher Chemosensor für diese Erkennung jedoch hauptverantwortlich ist, ist bisher unklar. In der vorliegenden Arbeit wurde die Rolle der Umamigeschmacksrezeptoruntereinheit Tas1r1 jenseits ihrer gustatorischen Bedeutung für die Aminosäuredetektion in der Mundhöhle untersucht.
In der histologischen Tas1r1-Expressionsanalyse nichtgustatorischer Gewebe der Mauslinie Tas1r1-Cre/ROSA26-tdRFP wurde über die Detektion des Reporterproteins tdRFP die Expression des Tas1r1 in allen untersuchten Geweben (Speiseröhre, Magen, Darm, Bauchspeicheldrüse, Leber, Niere, Muskel- und Fettgewebe, Milz, Thymus, Lymphknoten, Lunge sowie Hoden) nachgewiesen. Mit Ausnahme von Dünndarm und Hoden gelang hierbei der Nachweis erstmals spezifisch auf zellulärer Ebene. Caecum und Lymphknoten wurden zudem neu als Expressionsorte des Tas1r1 identifiziert.
Trotz der beobachteten weiten Verbreitung des Tas1r1 im Organismus – unter anderem auch in Geweben, die für den Proteinstoffwechsel besonders relevant sind – waren im Zuge der durchgeführten Untersuchung potentieller extraoraler Funktionen des Rezeptors durch phänotypische Charakterisierung der Mauslinie Tas1r1-BLiR nur schwache Auswirkungen auf Aminosäurestoffwechsel bzw. Stickstoffhaushalt im Falle eines Tas1r1-Knockouts detektierbar. Während sich Ernährungsverhalten, Gesamtphysiologie, Gewebemorphologie sowie Futterverdaulichkeit unverändert zeigten, war die renale Stickstoffausscheidung bei Tas1r1-Knockout-Mäusen auf eiweißarmer sowie auf eiweißreicher Diät signifikant verringert. Eine Überdeckung der Auswirkungen des Tas1r1-Knockouts aufgrund kompensatorischer Effekte durch den Aminosäuresensor CaSR oder den Peptidsensor Gpr93 war nicht nachweisbar. Es bleibt offen, ob andere Mechanismen oder andere Chemosensoren an einer Kompensation beteiligt sind oder aber Tas1r1 in extraoralem Gewebe andere Funktionen als die der Aminosäuredetektion übernimmt. Unterschiede im extraoralen Expressionsmuster der beiden Umamirezeptor-untereinheiten Tas1r1 und Tasr3 lassen Spekulationen über andere Partner, Liganden und Funktionen zu.
Zellbasierte heterologe Expressionssysteme bieten ein einfaches und schnelles Verfahren, um neue Süßstoffe oder Süßverstärker zu finden. Unter Verwendung eines solchen Testsystems, konnte ich in Zusammenarbeit mit der Symrise AG, Holzminden und dem Institut für Pflanzenbiochemie in Halle/Saale die vietnamesische Pflanze Mycetia balansae als Quelle eines neuen Süßstoffs identifizieren. Deren Hauptkomponenten, genannt Balansine, aktivieren spezifisch den humanen Süßrezeptor. Chimäre Rezeptoren zeigten, dass die amino-terminalen Domänen der Süßrezeptoruntereinheiten, welche ein Großteil der Liganden des Süßrezeptors binden, für dessen Aktivierung durch Balansin A nicht notwendig sind.
Voraussetzung für die Anwendung zellbasierter Testsysteme zum Auffinden neuer Süßstoffe ist jedoch, dass süße Substanzen gesichert identifiziert werden, während nicht süße Substanzen zuverlässig keine Rezeptoraktivierung aufweisen. Während in HEK293 TAS1R2 TAS1R3To Galpha15i3-Zellen Süßrezeptoraktivierung gegenüber nicht süß schmeckenden Substanzen beobachtet wurde, konnte mit den HEK293PEAKrapid Galpha15-Zellen ein zuverlässiges Testsystem identifiziert, welches den Süßgeschmack der untersuchten Substanzen widerspiegelte.
Es fanden sich keine Hinweise, dass akzessorische Proteine oder verwandte Rezeptoren des Süßrezeptors das unterschiedliche Verhalten der Zellen verursachen. Es konnte gezeigt werden, dass die Verwendung unterschiedlicher G-Proteine die Signalamplituden des Süßrezeptors beeinflusst, die Unterschiede zwischen den Zellsystemen jedoch nicht vollständig erklärt. Keine der untersuchten Galpha-Proteinchimären spiegelte die intrinsische Süße der Substanzen wider.
Wenn auch nicht ursächlich für die Diskrepanz zwischen Süßrezeptoraktivierung in vitro und Süßgeschmack in vivo, so weisen die Ergebnisse dieser Arbeit auf eine Interaktion der Süßrezeptoruntereinheiten mit dem humanen Calcium-sensing Rezeptor hin. Vanillin und Ethylvanillin konnten als neue Agonisten des Calcium-sensing Rezeptors identifiziert werden.
Wie die vorliegende Arbeit zeigt, können sich kleine Unterschiede im Zellhintergrund deutlich auf die Funktionsweise heterolog exprimierter Rezeptoren auswirken. Dies zeigt wie wichtig die Wahl der Zellen für solche Screeningsysteme ist.
Obesity is a major health problem for many developing and industrial countries. Increasing rates reach almost 50 % of the population in some countries and related metabolic diseases including cardiovascular events and T2DM are challenging the health systems. Adiposity, an increase in body fat mass, is a major hallmark of obesity. Adipose tissue is long known not only to store lipids but also to influence whole-body metabolism including food intake, energy expenditure and insulin sensitivity. Adipocytes can store lipids and thereby protect other tissue from lipotoxic damage. However, if the energy intake is higher than the energy expenditure over a sustained time period, adipose tissue will expand. This can lead to an impaired adipose tissue function resulting in higher levels of plasma lipids, which can affect other tissue like skeletal muscle, finally leading to metabolic complications. Several studies showed beneficial metabolic effects of weight reduction in obese subjects immediately after weight loss. However, weight regain is frequently observed along with potential negative effects on cardiovascular risk factors and a high intra-individual response.
We performed a body weight maintenance study investigating the mechanisms of weight maintenance after intended WR. Therefore we used a low caloric diet followed by a 12-month life-style intervention. Comprehensive phenotyping including fat and muscle biopsies was conducted to investigate hormonal as well as metabolic influences on body weight regulation. In this study, we showed that weight reduction has numerous potentially beneficial effects on metabolic parameters. After 3-month WR subjects showed significant weight and fat mass reduction, lower TG levels as well as higher insulin sensitivity. Using RNA-Seq to analyse whole fat and muscle transcriptome a strong impact of weight reduction on adipose tissue gene expression was observed. Gene expression alterations over weight reduction included several cellular metabolic genes involved in lipid and glucose metabolism as well as insulin signalling and regulatory pathways. These changes were also associated with anthropometric parameters assigning body composition. Our data indicated that weight reduction leads to a decreased expression of several lipid catabolic as well as anabolic genes. Long-term body weight maintenance might be influenced by several parameters including hormones, metabolic intermediates as well as the transcriptional landscape of metabolic active tissues. Our data showed that genes involved in biosynthesis of unsaturated fatty acids might influence the BMI 18-month after a weight reduction phase. This was further supported by analysing metabolic parameters including RQ and FFA levels. We could show that subjects maintaining their lost body weight had a higher RQ and lower FFA levels, indicating increased metabolic flexibility in subjects.
Using this transcriptomic approach we hypothesize that low expression levels of lipid synthetic genes in adipose tissue together with a higher mitochondrial activity in skeletal muscle tissue might be beneficial in terms of body weight maintenance.
Inflammation in Cachexia
(2015)
Epigenetic silencing of tumor suppressor genes is involved in early transforming events and has a high impact on colorectal carcinogenesis. Likewise, colon cancers that derive from chronically inflamed bowel diseases frequently exhibit epigenetic changes. But there is little data about epigenetic aberrations causing colorectal cancer in chronically inflamed tissue. The aim of the present study was to evaluate the aberrant gain of methylation in the gene promoters of VIM, TFPI2 and ITGA4 as putative early markers in the development from inflamed tissue via precancerous lesions toward colorectal cancer.
Initial screening of different cancer cell lines by using methylation-specific PCR revealed a putative colon cancer-specific methylation pattern. Additionally, a demethylation assay was performed to investigate the methylation-dependent gene silencing of ITGA4. The candidate markers were analyzed in colonic tissue specimens from patients with colorectal cancer (n = 15), adenomas (n = 76), serrated lesions (n = 13), chronic inflammation (n = 10) and normal mucosal samples (n = 9).
A high methylation frequency of VIM (55.6 %) was observed in normal colon tissue, whereas ITGA4 and TFPI2 were completely unmethylated in controls. A significant gain of methylation frequency with progression of disease as well as an age-dependent effect was detectable for TFPI2. ITGA4 methylation frequency was high in precancerous and cancerous tissues as well as in inflammatory bowel diseases (IBD).
The already established methylation marker VIM does not permit a specific and sensitive discrimination of healthy and neoplastic tissue. The methylation markers ITGA4 and TFPI2 seem to be suitable risk markers for inflammation-associated colon cancer.
Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
Im Rahmen der EU-weiten REACH-Verordnung haben Alternativmethoden zum Tierversuch in der Toxikologie an Bedeutung gewonnen. Die Alternativmethoden gliedern sich auf in In-vitro- und In-silico-Methoden. In dieser Dissertation wurden verschiedene Konzepte der In-silico-Toxikologie behandelt.
Die bearbeiteten Themen reichen von quantitativen Strukturaktivitätsbeziehungen (QSAR) über eine neue Herangehensweise an das gängige Konzept zur Festlegung von Grenzwerten bis hin zu computerbasierten Modellierungen zum Alkohol- und Bisphenol-A-Stoffwechsel.
Das Kapitel über QSAR befasst sich im Wesentlichen mit der Erstellung und Analyse einer Datenbank mit 878 Substanzen, die sich aus Tierversuchsstudien aus dem Archiv des Bundesinstituts für Risikobewertung zusammensetzt. Das Design wurde dabei an eine bereits bestehende Datenbank angepasst, um so einen möglichst großen Datenpool zu generieren. In der Analyse konnte u.a. gezeigt werden, dass Stoffe mit niedrigerem Molekulargewicht ein erhöhtes Potential für toxikologische Schäden aufwiesen als größere Moleküle.
Mit Hilfe des sogenannten TTC-Konzepts können Grenzwerte für Stoffe geringer Exposition festgelegt werden, zu denen keine toxikologischen Daten zur Verfügung stehen. In dieser Arbeit wurden für die Stoffe dreier Datenbanken entsprechende Grenzwerte festgelegt. Es erfolgte zunächst eine gängige strukturbasierte Aufteilung der Substanzen in die Kategorien "nicht toxisch", "möglicherweise toxisch" und "eindeutig toxisch". Substanzen, die aufgrund ihrer Struktur in eine der drei Klassen eingeordnet werden, erhalten den entsprechenden Grenzwert. Da in die dritte Klasse auch Stoffe eingeordnet werden, deren Toxizität nicht bestimmbar ist, ist sie sehr groß. Daher wurden in dieser Arbeit die ersten beiden Klassen zusammengelgt, um einen größeren Datenpool zu ermöglichen. Eine weitere Neuerung umfasst die Erstellung eines internen Grenzwerts. Diese Vorgehensweise hat den Vorteil, dass der Expositionsweg herausgerechnet wird und somit beispielsweise Studien mit oraler Verabreichung mit Studien dermaler Verabreichung verglichen werden können.
Mittels physiologisch basiertem kinetischem Modelling ist es möglich, Vorgänge im menschlichen Körper mit Hilfe spezieller Software nachzuvollziehen. Durch diese Vorgehensweise können Expositionen von Chemikalien simuliert werden. In einem Teil der Arbeit wurden Alkoholexpositionen von gestillten Neugeborenen simuliert, deren Mütter unmittelbar zuvor alkoholische Getränke konsumiert hatten. Mit dem Modell konnte gezeigt werden, dass die Expositionen des Kindes durchweg gering waren. Nach einem Glas Wein wurden Spitzenkonzentrationen im Blut von Neugeborenen von 0,0034 Promille ermittelt. Zum Vergleich wurde die Exposition durch ein für Säuglinge zugelassenes alkoholhaltiges pflanzliches Arzneimittel simuliert. Hier wurden Spitzenkonzentrationen von 0,0141 Promille erreicht. Daher scheinen Empfehlungen wie gelegentlicher Konsum ohne schädigende Wirkung auf das Kind wissenschaftlich fundiert zu sein.
Ein weiteres Kinetik-Modell befasste sich mit dem Stoffwechsel von Bisphenol A. Teils widersprüchliche Daten zur Belastung mit BPA in der wissenschaftlichen Literatur führen wiederholt zu Anregungen, den Grenzwert der Chemikalie anzupassen. Die Funktionalität der am Metabolismus beteiligten Enzyme kann je nach Individuum unterschiedlich ausgeprägt sein. Mittels Modellings konnte hier gezeigt werden, dass dies maßgeblich dazu führt, dass sich berechnete Plasmaspiegel von Individuen bis zu 4,7-fach unterscheiden.
Die Arbeit konnte somit einen Beitrag zur Nutzung und Weiterentwicklung von In-silico-Modellen für diverse toxikologische Fragestellungen leisten.
The stems of Abrus precatorius were used to extract a beta-amylase enriched fraction. A three phase partitioning method and a Doehlert design with 3 variables (ratio of crude extract/t-butanol, the ammonium sulphate saturation and pH) were used. The data was fitted in a second-order polynomial model and the parameters were optimized to enrich beta-amylase. Experimental responses for the modulation were recovery of activity and the purification factor. The optimal conditions were: a ratio of crude extract/t-butanol of 0.87 (v/v), saturation in ammonium sulphate of 49.46% (w/v) and a pH of 5.2. An activity recovery of 156.2% and a purification factor of 10.17 were found. The enriched enzyme was identified as a beta-amylase and its molecular weight was 60.1 kDa. K-m and V-max values were 79.37 mg/ml and 5.13 U/ml, respectively and the highest activity was registered at a temperature of 70 degrees C and a pH between 6 and 6.5. A significant stabilization of the beta-amylase was observed up to 65 degrees C. (C) 2015 Elsevier Ltd. All rights reserved.
Iron deficiency anemia, zinc and vitamin A deficiencies are serious public health problems in Cameroon, as in many developing countries. Local vegetables which are sources of provitamin A carotenoids (PACs) can be used to improve vitamin A intakes. However, traditional meals are often unable to cover zinc and iron needs. The aim of this study was to determine the bioavailability of 3 PACs (alpha-carotene, beta-carotene, and beta-cryptoxanthin) in young men, who were fed with a vitamin A-free diet and received iron and zinc supplementation. Twelve healthy participants were divided into three groups and were supplemented with elemental iron (20 mg of iron fumarate), 20 mg of zinc sulfate or iron + zinc (20 mg of iron in the morning and 20 mg of zinc in the evening) for 11 d. They were given a vitamin A- and PAC-free diet from the 6th to the 11th day, followed by a test meal containing 0.55 kg of freshly peeled papaya as a source of PACs. Blood samples were collected four times successively on the 11th day (the test meal day), at TO (just after the test meal), after 2 h (T2), after 4 h (T4) and after 7 h (T7). Ultracentrifugation was used to isolate serum chylomicrons. Retinol appearance and PAC postprandial concentrations were determined. The supplementation with zinc, iron and iron+zinc influenced the chylomicron appearance of retinol and PACs differently as reflected by retention times and maximum absorption peaks. Iron led to highest retinol levels in the chylomicron. Zinc and iron+zinc supplements were best for optimal intact appearance of alpha-carotene, beta-carotene and beta-cryptoxanthin respectively. Supplementation with iron led to the greatest bioavailability of PACs from papaya and its conversion to retinol.
Background: Sub-Saharan Africa is facing a double burden of malnutrition: vitamin A deficiency (VAD) prevails, whereas the nutrition-related chronic conditions type 2 diabetes (T2D) and hypertension are emerging. Serum retinol a VAD marker increases in kidney disease and decreases in inflammation, which can partly be attributed to alterations in the vitamin A transport proteins retinol-binding protein 4 (RBP4) and prealbumin. Kidney dysfunction and inflammation commonly accompany T2D and hypertension.
Objective: Among urban Ghanaians, we investigated the associations of T2D and hypertension with serum retinol as well as the importance of kidney function and inflammation in this regard.
Design: A hospital-based, case-control study in individuals for risk factors of T2D, hypertension, or both was conducted in Kumasi, Ghana (328 controls, 197 with T2D, 354 with hypertension, and 340 with T2D plus hypertension). In 1219 blood samples, serum retinol, RBP4, and prealbumin were measured. Urinary albumin and estimated glomerular filtration rate (eGFR) defined kidney function. C-reactive protein (CRP) >5 mg/L indicated inflammation. We identified associations of T2D and hypertension with retinol by linear regression and calculated the contribution of RBP4, prealbumin, urinary albumin, eGFR, and CRP to these associations as the percentages of the explained variance of retinol.
Results: VAD (retinol <1.05 mu mol/L) was present in 10% of this predominantly female, middle-aged, overweight, and deprived population. Hypertension, but not T2D, was positively associated with retinol (beta: 0.12; 95% CI: 0.08, 0,17), adjusted for age, sex, socioeconomic factors, anthropometric measurements, and lifestyle. In addition to RBP4 (72%) and prealbumin (22%), the effect of increased retinol on individuals with hypertension was mainly attributed to impaired kidney function (eGFR: 30%; urinary albumin: 5%) but not to inflammation.
Conclusions: In patients with hypertension, VAD might be underestimated because of increased serum retinol in the context of kidney dysfunction. Thus, the interpretation of serum retinol in sub-Saharan Africa should account for hypertension status.
CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.
Objectives: This study aims to increase understanding of the connection between oxidative stress and inflammation in diabetes disease progression to provide a basis for investigating improved diagnostic possibilities, treatment and prevention of prediabetes.
Design and methods: Differences in the level of biochemical markers of oxidative stress (erythrocyte GSH/GSSG and urinary 8-isoprostane), inflammation (CRP, IL-6), endothelial dysfunction (plasma homocysteine, urinary 8-hydroxy-2-deoxy-guanosine) and coagulation/fibrinolysis (C5a, D-Dimer) were determined in prediabetes and control subjects.
Results: While no difference was found in the 8-isoprostane levels between the two groups, the erythrocyte GSH/GSSG ratio was significantly reduced in the prediabetes group compared to control, indicating increased oxidative stress in the prediabetic state. Both urinary 8-OHdG and surprisingly also plasma homocysteine were significantly elevated in the prediabetes group, indicating endothelial dysfunction. The inflammation markers were slightly elevated in the prediabetic subjects and the same trend was found for the coagulation/fibrinolysis markers C5a and D-Dimer. These results were however not significant.
Conclusions: The small elevation of blood glucose levels in the prediabetic state may have a detectable influence on endothelial function as indicated by changes to 8-OHdG, indicating an increased DNA-damage and homocysteine release from endothelial cells. Increased oxidative stress as indicated by the reduced GSH/GSSG ratio is likely to be the link between the moderate hyperglycaemia in prediabetes and pathological changes in endothelial function, which in the long-term may promote atherogenesis and result in the development of cardiovascular disease. Early detection of prediabetes is essential to avoid diabetes development and the associated complications like cardiovascular disease. The GSH/GSSG ratio and biomarkers like urinary 8-OHdG and plasma homocysteine offer a possible tool for the assessment of prediabetes in prevention screenings. (C) 2015 The Authors. The Canadian Society of Clinical Chemists. Published by Elsevier Inc.
The role of serum amyloid A and sphingosine-1-phosphate on high-density lipoprotein functionality
(2015)
The high-density lipoprotein (HDL) is one of the most important endogenous cardiovascular protective markers. HDL is an attractive target in the search for new pharmaceutical therapies and in the prevention of cardiovascular events. Some of HDL's anti-atherogenic properties are related to the signaling molecule sphingosine-1-phosphate (S1P), which plays an important role in vascular homeostasis. However, for different patient populations it seems more complicated. Significant changes in HDL's protective potency are reduced under pathologic conditions and HDL might even serve as a proatherogenic particle. Under uremic conditions especially there is a change in the compounds associated with HDL. S1P is reduced and acute phase proteins such as serum amyloid A (SAA) are found to be elevated in HDL. The conversion of HDL in inflammation changes the functional properties of HDL. High amounts of SAA are associated with the occurrence of cardiovascular diseases such as atherosclerosis. SAA has potent pro-atherogenic properties, which may have impact on HDL's biological functions, including cholesterol efflux capacity, antioxidative and anti-inflammatory activities. This review focuses on two molecules that affect the functionality of HDL. The balance between functional and dysfunctional HDL is disturbed after the loss of the protective sphingolipid molecule S1P and the accumulation of the acute-phase protein SAA. This review also summarizes the biological activities of lipid-free and lipid-bound SAA and its impact on HDL function.
Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAL-I. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. (C) 2015 Elsevier Inc. All rights reserved.
Background: The objective of the study was to investigate the relationship between first trimester maternal serum levels of the TTR-RBP4-ROH complex components and the later insurgence of an altered glucose metabolism during pregnancy.
Methods: Retrospective case control study including 96 patients between the 12th and 14th week of gestation, 32 that developed gestational diabetes mellitus (GDM), respectively, 21 non-insulin-treated (dGDM) and 11 insulin-treated (iGDM), 20 large for gestational age fetuses (LGA) without GDM and 44 patients with normal outcome as control. Serum concentrations of RBP4 and TTR were assessed by ELISA; serum concentration of ROH by reverse-phase high performance liquid chromatography (rpHPLC). The molecular heterogeneity of TTR and RBP4 was analyzed after immunoprecipitation by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS).
Results: iGDM patients were characterized by reduced TTR, RBP4 and ROH compared to controls (respectively, iGDM vs. controls, mean +/- SD: TTR 3.96 +/- 0.89 mu mol/L vs. 4.68 +/- 1.21 mu mol/L, RBP4 1.13 +/- 0.25 mu mol/L vs. 1.33 +/- 0.38 mu mol/L and ROH 1.33 +/- 0.17 mu mol/L vs. 1.62 +/- 0.29 mu mol/L, p < 0.05). TTR containing Gly10 in place of Cys10 was lower in the iGDM group (p < 0.05) compared to controls. In the final logistic regression model ROH significantly predicted the diagnosis of iGDM (OR 0.93, 95% CI 0.87-0.98, p < 0.05).
Conclusions: First trimester maternal serum ROH, RBP4 and TTR represent potential biomarkers associated with the development of iGDM.