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Background: Plasma concentration of retinol is an accepted indicator to assess the vitamin A (retinol) status in cattle. However, the determination of vitamin A requires a time consuming multi-step procedure, which needs specific equipment to perform extraction, centrifugation or saponification prior to high-performance liquid chromatography (HPLC).
Methods: The concentrations of retinol in whole blood (n = 10), plasma (n = 132) and serum (n = 61) were measured by a new rapid cow-side test (iCheck™ FLUORO) and compared with those by HPLC in two independent laboratories in Germany (DE) and Japan (JP).
Results: Retinol concentrations in plasma ranged from 0.033 to 0.532 mg/L, and in serum from 0.043 to 0.360 mg/L (HPLC method). No significant differences in retinol levels were observed between the new rapid cow-side test and HPLC performed in different laboratories (HPLC vs. iCheck™ FLUORO: 0.320 ± 0.047 mg/L vs. 0.333 ± 0.044 mg/L, and 0.240 ± 0.096 mg/L vs. 0.241 ± 0.069 mg/L, lab DE and lab JP, respectively). A similar comparability was observed when whole blood was used (HPLC vs. iCheck™ FLUORO: 0.353 ± 0.084 mg/L vs. 0.341 ± 0.064 mg/L). Results showed a good agreement between both methods based on correlation coefficients of r2 = 0.87 (P < 0.001) and Bland-Altman blots revealed no significant bias for all comparison.
Conclusions: With the new rapid cow-side test (iCheck™ FLUORO) retinol concentrations in cattle can be reliably assessed within a few minutes and directly in the barn using even whole blood without the necessity of prior centrifugation. The ease of the application of the new rapid cow-side test and its portability can improve the diagnostic of vitamin A status and will help to control vitamin A supplementation in specific vitamin A feeding regimes such as used to optimize health status in calves or meat marbling in Japanese Black cattle.
Mutations in the gene encoding for filaggrin (FLG) are major predisposing factors for atopic dermatitis (AD). Besides genetic predisposition, immunological dysregulations considerably contribute to its pathophysiology. For example, thymic stromal lymphopoietin (TSLP) is highly expressed in lesional atopic skin and significantly contributes to the pathogenesis of AD by activating dendritic cells that then initiate downstream effects on, for example, T cells. However, little is known about the direct interplay between TSLP, filaggrin-deficient skin and other immune cells such as T lymphocytes. In the present study, FLG knockdown skin equivalents, characterised by intrinsically high TSLP levels, were exposed to activated CD4(+) T cells. T cell exposure resulted in an inflammatory phenotype of the skin equivalents. Furthermore, a distinct shift from a Th1/Th17 to a Th2/Th22 profile was observed following exposure of T cells to filaggrin-deficient skin equivalents. Interestingly, TSLP directly stimulated T cell migration exclusively in filaggrin-deficient skin equivalents even in the absence of dendritic cells, indicating a hitherto unknown role of TSLP in the pathogenesis of AD.
Small selenium (Se) species play a major role in the metabolism, excretion and dietary supply of the essential trace element selenium. Human cells provide a valuable tool for investigating currently unresolved issues on the cellular mechanisms of Se toxicity and metabolism. In this study, we developed two isotope dilution inductively coupled plasma tandem-mass spectrometry based methods and applied them to human hepatoma cells (HepG2) in order to quantitatively elucidate total cellular Se concentrations and cellular Se species transformations in relation to the cytotoxic effects of four small organic Se species. Species-and incubation time-dependent results were obtained: the two major urinary excretion metabolites trimethylselenonium (TMSe) and methyl-2-acetamido-2-deoxy-1-seleno-beta- D-galactopyranoside (SeSugar 1) were taken up by the HepG2 cells in an unmodified manner and did not considerably contribute to the Se pool. In contrast, Se-methylselenocysteine (MeSeCys) and selenomethionine (SeMet) were taken up in higher amounts, they were largely incorporated by the cells (most likely into proteins) and metabolized to other small Se species. Two new metabolites of MeSeCys, namely gamma-glutamyl-Se-methylselenocysteine and Se-methylselenoglutathione, were identified by means of HPLC-electrospray-ionization-Orbitrap-MS. They are certainly involved in the (de-) toxification modes of Se metabolism and require further investigation.
Arsenolipids are lipid-soluble organoarsenic compounds, mainly occurring in marine organisms, with arsenic-containing hydrocarbons (AsHCs) and arsenic-containing fatty acids (AsFAs) representing two major subgroups. Recently, toxicity studies of several arsenolipids showed a high cytotoxic potential of those arsenolipids in human liver and bladder cells. Furthermore, feeding studies with Drosophila melanogaster indicated an accumulation of arsenolipids in the fruit fly’s brain. In this study, the neurotoxic potential of three AsHCs, two AsFAs and three metabolites (dimethylarsinic acid, thio/oxo-dimethylarsenopropanoic acid) was investigated in comparison to the toxic reference arsenite (iAsIII) in fully differentiated human brain cells (LUHMES cells). Thereby, in the case of AsHCs both the cell number and cell viability were reduced in a low micromolar concentration range comparable to iAsIII, while AsFAs and the applied metabolites were less toxic. Mechanistic studies revealed that AsHCs reduced the mitochondrial membrane potential, whereas neither iAsIII nor AsFAs had an impact. Furthermore, neurotoxic mechanisms were investigated by examining the neuronal network. Here, AsHCs massively disturbed the neuronal network and induced apoptotic effects, while iAsIII and AsFAs showed comparatively lesser effects. Taking into account the substantial in vitro neurotoxic potential of the AsHCs and the fact that they could transfer across the physiological barriers of the brain, a neurotoxic potential in vivo for the AsHCs cannot be excluded and needs to be urgently characterized.
A novel method based on liquid-liquid extraction with subsequent gas chromatography separation and mass spectrometric detection (GC-MS) for the quantification of organic carbonates in cell culture materials is presented. Method parameters including the choice of extraction solvent, of extraction method and of extraction time were optimised and the method was validated. The setup allowed for determination within a linear range of more than two orders of magnitude. The limits of detection (LODs) were between 0.0002 and 0.002 mmol/L and the repeatability precisions were in the range of 1.5-12.9%. It could be shown that no matrix effects were present and recovery rates between 98 and 104% were achieved. The methodology was applied to cell culture models incubated with commercial lithium ion battery (LIB) electrolytes to gain more insight into the potential toxic effects of these compounds. The stability of the organic carbonates in cell culture medium after incubation was studied. In a porcine model of the blood-cerebrospinal fluid (CSF) barrier, it could be shown that a transfer of organic carbonates into the brain facing compartment took place.
Investigations on the post mortal formation of fluorescent zinc protoporphyrin (ZnPP) IX in pork meat are currently in focus of meat science research. The role of myoglobin degradation in this context appears to be one of the most diversely discussed issues. To address this question meat-extracts of longissimus lumborum (LL) muscle (0.8 mg/mL) were incubated at 30 degrees C for up to 72 h and investigated by HPSEC-UV-fluorescence, SDS-PAGE and MALDI-TOF-MS. Between 0 and 72 h of incubation the fluorescence intensity (lambda(ex)./(em). = 420/590 nm) of the meat-extracts rose significantly (p < 0.001) from 10.9 +/- 0.8 to 34.8 +/- 0.3 (rel. units) while the staining intensity of the SDS-PAGE of myoglobin non-significantly (p > 0.4) changed from 6.2 +/- 0.5 x 105 to 5.0 +/- 0.3 x 105 (rel. units). The results indicate that ZnPP is formed by a Fe(II)-Zn(II)-substitution in myoglobin heme where an accompanying myoglobin degradation is not necessarily obligatory. (C) 2017 Elsevier Ltd. All rights reserved.
BACKGROUNDProduction and the quality of tomato fruits have a strong economic relevance. Microorganisms such as the plant growth-promoting bacterium (PGPB) Kosakonia radicincitans (DSM 16656) have been demonstrated to improve shoot and root growth of young tomato plants, but data on yield increase and fruit quality by K. radicincitans are lacking. RESULTSThis study investigated how K. radicincitans affects tomato fruits. After inoculation of tomato seeds with K. radicincitans or a sodium chloride buffer control solution, stalk length, first flowering and the amount of ripened fruits produced by inoculated and non-inoculated plants were monitored over a period of 21 weeks. Inoculation of tomato seeds with K. radicincitans accelerated flowering and ripening of tomato fruits. Sugars, acidity, amino acids, volatile organic compounds and carotenoids in the fruits were also analyzed. CONCLUSIONIt was found that the PGPBK. radicincitans affected the amino acid, sugar and volatile composition of ripened fruits, contributing to a more pleasant-tasting fruit without forfeiting selected quality indicators. (c) 2017 Society of Chemical Industry
Single-cell analysis by ICP-MS/MS as a fast tool for cellular bioavailability studies of arsenite
(2017)
Single-cell inductively coupled plasma mass spectrometry (SC-ICP-MS) has become a powerful and fast tool to evaluate the elemental composition at a single-cell level. In this study, the cellular bioavailability of arsenite (incubation of 25 and 50 mu M for 0-48 h) has been successfully assessed by SC-ICP-MS/MS for the first time directly after re-suspending the cells in water. This procedure avoids the normally arising cell membrane permeabilization caused by cell fixation methods (e.g. methanol fixation). The reliability and feasibility of this SC-ICP-MS/MS approach with a limit of detection of 0.35 fg per cell was validated by conventional bulk ICP-MS/MS analysis after cell digestion and parallel measurement of sulfur and phosphorus.
Quantitative determination of the sulfur-containing antioxidant ergothioneine by HPLC/ICP- QQQ-MS
(2017)
Interest in the sulfur-containing antioxidant ergothioneine calls for reliable analytical methods for its quantification. In this work, a method based on reversed-phase high performance liquid chromatography (RP-HPLC) coupled with elemental mass spectrometry detection in mass shift mode (inductively coupled plasma triple quadrupole mass spectrometry, ICP-QQQ-MS) using oxygen as the reaction gas was developed for the element-selective determination of ergothioneine in complex biological matrices. Application of an instrumental setup using a 6-port-valve and the introduction of a methanol gradient allowed the time-efficient analysis of samples containing strongly retained sulfur species besides ergothioneine without compromising ICPMS detection. In aqueous solution, limits of detection and quantification (LOD and LOQ) of the optimized method for m/z 32 -> 48 (SO+) were 0.23 mu g S per L and 0.80 mu g S per L, respectively; measurements in a complex matrix (human hepatocyte carcinoma cells, HepG2) resulted in an LOD of 0.6 mu g S per L and an LOQ of 2.3 mu g S per L. Recoveries of ergothioneine from cell pellets spiked with the analyte before cell lysis (97 +/- 3%) matched those obtained for cell culture medium spiked before syringe filtration (96 +/- 9%) demonstrating that sample preparation did not impair the quantitative determination of ergothioneine. When HepG2 cells were exposed to ergothioneine via the culture medium, they showed low absorption; approximately 3% of the added ergothioneine was found in cell lysates, while most of it (>= 85%) remained in the cell culture medium. The method is capable of separating ergothioneine from other biologically relevant sulfur-containing species and is expected to be of broad future use. Furthermore, the potential use for the simultaneous separation of selenium species, thereby extending the scope of possible applications, was demonstrated by applying it to water extracts of oyster mushrooms.
Background/Aims: Contrast induced acute kidney injury (CI-AKI) remains a serious complication of contrast media enhanced procedures like coronary angiography. There is still a lack of established biomarkers that help to identify patients at high risk for short and long-term complications. The aim of the current study was to evaluate plasma kynurenine as a predictive biomarker for CI-AKI and long-term complications, measured by the combined endpoint "major adverse kidney events" (MAKE) up to 120 days after CM application.
Methods: In this prospective cohort study 245 patients undergoing coronary angiography were analyzed. Blood samples were obtained at baseline, 24h and 48h after contrast media (CM) application to diagnose CI-AKI. Patients were followed for 120 days for adverse clinical events including death, the need for dialysis, and a doubling of plasma creatinine. Occurrence of any of these events was summarized in the combined endpoint MAKE.
Results: Preinterventional plasma kynurenine was not associated with CI-AKI. Patients who later developed MAKE displayed significantly increased preinterventional plasma kynurenine levels (p<0.0001). ROC analysis revealed that preinterventional kynurenine is highly predictive for MAKE (AUC=0.838; p<0.0001). The optimal cutoff was found at >= 3.5 mu mol/L. Using this cutoff, the Kaplan-Meier estimator demonstrated that concentrations of plasma kynurenine >= 3.5 mu mol/L were significantly associated with a higher prevalence of MAKE until follow up (p<0.0001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome.
Conclusion: Preinterventional plasma kynurenine might serve as a highly predictive biomarker for MAKE up to 120 days after coronary angiography.
Background/Aims:
The ET system might be involved in the pathogenesis of hypertensive disorders during pregnancy. The objective is to analyse the impact of ET-1 in hypertensive pregnant women by a strict meta-analysis of published human clinical studies.
Methods:
Based on the principle of Cochrane systematic reviews, Cohort studies in PubMed (Medline), Google Scholar and China Biological Medicine Database (CBM-disc) designed to identify the role of endothelin-1 (ET-1) in the pathophysiology of gestational hypertension and preeclampsia were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects model.
Results:
Sixteen published cohort studies including 1739 hypertensive cases and 409 controls were used in the meta-analysis. ET-1 plasma concentrations were higher in hypertensive pregnant women as compared to the controls (mean difference between groups: 19.02 [15.60~22.44], P < 0.00001,). These finding were driven by severity of hypertension and/or degree of proteinuria.
Conclusion:
Plasma ET-1 concentrations are elevated in hypertensive disorders during human pregnancy. In particular women with preeclampsia (hypertensive pregnant women with proteinuria) have substantially elevated plasma ET-1 concentration as compared to pregnant women with normal blood pressure.
Background/Aims: A recent study revealed that global overexpression of ET-1 causes a slight reduction in systemic blood pressure. Moreover, heterozygous ET-1 knockout mice are hypertensive. The role of ET-1 in human hypertension was so far not addressed by a strict meta-analysis of published human clinical studies.
Methods: We included studies published between January 1, 1990 and February 28, 2017. We included case control studies analyzing untreated essential hypertension or hypertensive patients where antihypertensive medication was discontinued for at least two weeks. Based on the principle of Cochrane systematic reviews, case control studies (CCSs) in PubMed (Medline) and Google Scholar designed to identify the role of endothelin-1 (ET-1) in the pathophysiological of hypertension were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects models.
Results: Eleven studies fulfilling our in-and exclusion criteria were eligible for this meta-analysis. These studies included 450 hypertensive patients and 328 controls. Our meta-analysis revealed that ET-1 plasma concentrations were higher in hypertensive patients as compared to the control patients [mean difference between groups 1.57 pg/mL, 95%Ci [0.47 similar to 2.68, P = 0.005]. These finding were driven by patients having systolic blood pressure higher than 160 mmHg and diastolic blood pressure higher than 100 mmHg.
Conclusions: This meta-analysis showed that hypertensive patients do have elevated plasma ET-1 concentrations. This finding is driven by those patients with high systolic/diastolic blood pressure. Given that the ET-1 gene did not appear in any of the whole genome association studies searching for hypertension associated gene loci, it is very likely that the elevated plasma ET-1 concentrations in hypertensive patients are secondary to hypertension and may reflect endothelial cell damage.
A balanced sphingolipid rheostat is indispensable for dendritic cell function and survival and thus initiation of an immune response. Sphingolipid levels are dynamically maintained by the action of sphingolipid enzymes of which sphingosine kinases, S1P phosphatases (SGPP-1/2) and S1P lyase (SGPL-1), are pivotal in the balance of S1P and sphingosine levels. In this study, we present that SGPP-1 and SGPL-1 are regulated in inflammatory dendritic cells and contribute to S1P fate. TLR-dependent activation caused SGPL-1 protein downregulation with subsequent decrease of enzymatic activity by two-thirds. In parallel, confocal fluorescence microscopy revealed that endogenous SGPP-1 was expressed in nuclei of naive dendritic cells and was translocated into the cytoplasmatic compartment upon inflammatory stimulation resulting in dephosphorylation of S1P. Mass spectrometric determination showed that a part of the resulting sphingosine was released from the cell, increasing extracellular levels. Another route of diminishing intracellular S1P was possibly taken by its export via ATP-binding cassette transporter C1 which was upregulated in array analysis, while the S1P transporter, spinster homolog 2, was not relevant in dendritic cells. These investigations newly describe the sequential expression and localization of the endogenous S1P regulators SGPP-1 and SGPL-1 and highlight their contribution to the sphingolipid rheostat in inflammation.
Carotenoids are lipid-soluble pigments and important for a variety of physiological functions. They are major dietary vitamin A precursors and act as lipophilic antioxidants in a variety of tissues and are associated with important health benefits in humans and animals. All animals must acquire carotenoids from their diet, but to our knowledge, there are no studies investigating the intestinal carotenoid absorption and their blood concentrations in New World camelids. The present study aimed to assess the serum concentrations of selected carotenoids in llamas (n=13) and alpacas (n=27). Serum carotenoids as well as retinol (vitamin A) and -tocopherol (vitamin E) were determined by high-performance liquid chromatography coupled with mass spectrometry and these were unable to detect any carotenoids (- and -carotene, - and -cryptoxanthin, lutein, zeaxanthin, lycopene) in the samples. The concentrations of retinol in alpacas (2.89 +/- 1.13mol/l; mean +/- SD) were higher (p=0.024) than those found in llamas (2.05 +/- 0.87mol/l); however, the concentrations of -tocopherol were not significantly (p=0.166) different (llamas: 3.98 +/- 1.83mol/l; alpacas: 4.95 +/- 2.14mol/l). The results show that both llamas and alpacas are not able to absorb intact carotenoids, but efficiently convert provitamin A carotenoids to retinol.
Strong experimental evidence in animal and cellular models supports a pivotal role of sphingosine kinase-1 (SK1) in oncogenesis. In many human cancers, SK1 levels are upregulated and these increases are linked to poor prognosis in patients. Here, by employing untargeted NMR- based metabolomic profiling combined with functional validations, we report the crucial role of SK1 in the metabolic shift known as the Warburg effect in A2780 ovarian cancer cells. Indeed, expression of SK1 induced a high glycolytic rate, characterized by increased levels of lactate along with increased expression of the proton/monocarboxylate symporter MCT1, and decreased oxidative metabolism, associated with the accumulation of intermediates of the tricarboxylic acid cycle and reduction in CO2 production. Additionally, SK1-expressing cells displayed a significant increase in glucose uptake paralleled by GLUT3 transporter upregulation. The role of SK1 is not limited to the induction of aerobic glycolysis, affecting metabolic pathways that appear to support the biosynthesis of macromolecules. These findings highlight the role of SK1 signaling axis in cancer metabolic reprogramming, pointing out innovative strategies for cancer therapies.
Within the last few decades, liquid chromatography-mass spectrometry (LC-MS) has become a preferred method for manifold issues in analytical biosciences, given its high selectivity and sensitivity. However, the analysis of fatty aldehydes, which are important components of cell metabolism, remains challenging. Usually, chemical derivatization prior to MS detection is required to enhance ionization efficiency. In this regard, the coupling of fatty aldehydes to hydrazines like 2,4-dinitrophenylhydrazine (DNPH) is a common approach. Additionally, hydrazones readily react with fatty aldehydes to form stable derivatives, which can be easily separated using high-performance liquid chromatography (HPLC) and subsequently detected by MS. Here, we exemplarily present the quantification of the long-chain fatty aldehyde (2E)-hexadecenal, a break-down product of the bioactive lipid sphingosine 1-phosphate (S1P), after derivatization with 2-diphenylacetyl-1,3-indandione-1-hydrazone (DAIH) via isotope-dilution HPLC-electrospray ionization-quadrupole/time-of-flight (ESI-QTOF) MS. Moreover, we show that the addition of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) as a coupling agent allows for simultaneous determination of fatty aldehydes and fatty acids as DAIH derivatives. Taking advantage of this, we describe in detail how to monitor the degradation of (2E)-hexadecenal and the concurrent formation of its oxidation product (2E)-hexadecenoic acid in lysates of human hepatoblastoma (HepG2) cells within this chapter.
Background/Aims:
Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6).
Methods:
The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS).
Results:
Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25).
Conclusion:
LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity.
Lutein is an essential dietary carotenoid with health benefits and is inter alia responsible for the colouration of egg yolk. The relationship between lutein accumulation and egg yolk colouration was therefore studied in more detail. After feeding a low-luteine diet for 21 days, 14 birds (Lohmann brown hens aged 20 weeks) were fed a diet containing marigold (80 mg lutein/kg feed) and 14 other birds were fed a diet containing oleoresin (45 mg lutein/kg feed) for 21 days; for both groups of birds, this feeding period was followed by withdrawal for 21 days. The Roche Yolk Colour Fan (RYCF) score (0 to 15, where higher values denote greater colour intensity; R-2=0.87; P<0.01) and redness (R-2=0.89; P<0.01) increased with increasing lutein content of egg yolk. Total carotenoid content had a poor relationship with lightness (R-2=0.13; P>0.05) and yellowness (R-2=0.12; P>0.05) of the yolk. It may be concluded that increased lutein is potentially responsible for an increased RYCF score and redness (a*), but decreased yellowness (b*) and lightness (L*), of egg yolk.
The degeneration of the retinal pigment epithelium caused by oxidative damage is a stage of development in age related macular degeneration (AMD). The carotenoid lutein is a major macular pigment that may reduce the incidence and progression of AMD, but the underlying mechanism is currently not fully understood. Carotenoids are known to be direct antioxidants. However, carotenoids can also activate cellular pathways resulting in indirect antioxidant effects. Here, we investigate the influence of lutein on the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) target genes in human retinal pigment epithelial cells (ARPE-19 cells) using lutein-loaded Tween40 micelles. The micelles were identified as a suitable delivery system since they were nontoxic in APRE-19 cells up to 0.04% Tween40 and led to a cellular lutein accumulation of 62 mu M +/- 14 mu M after 24 h. Lutein significantly enhanced Nrf2 translocation to the nucleus 1.5 +/- 0.4-fold compared to that of unloaded micelles after 4 h. Furthermore, lutein treatment for 24 h significantly increased the transcripts of NAD(P)H:quinone oxidoreductase 1 (NQO1) by 1.7 +/- 0.1-fold, glutamate-cysteine ligase regulatory subunit (GCLm) by 1.4 +/- 0.1-fold, and heme oxygenase-1 (HO-1) by 1.8 +/- 0.3-fold. Moreover, we observed a significant enhancement of NQO1 activity by 1.2 +/- 0.1-fold. Collectively, this study indicates that lutein not only serves as a direct antioxidant but also activates Nrf 2 in ARPE-19 cells.
Aims: The MARLINA-T2D study (ClinicalTrials. gov, NCT01792518) was designed to investigate the glycaemic and renal effects of linagliptin added to standard-of-care in individuals with type 2 diabetes and albuminuria. Methods: A total of 360 individuals with type 2 diabetes, HbA1c 6.5% to 10.0% (48-86 mmol/ mol), estimated glomerular filtration rate (eGFR) >= 30 mL/min/1.73 m(2) and urinary albumin-tocreatinine ratio (UACR) 30-3000 mg/g despite single agent renin-angiotensin-system blockade were randomized to double-blind linagliptin (n = 182) or placebo (n = 178) for 24 weeks. The primary and key secondary endpoints were change from baseline in HbA1c at week 24 and time-weighted average of percentage change from baseline in UACR over 24 weeks, respectively. Results: Baseline mean HbA1c and geometric mean (gMean) UACR were 7.8% +/- 0.9% (62.2 +/- 9.6 mmol/mol) and 126 mg/g, respectively; 73.7% and 20.3% of participants had microalbuminuria or macroalbuminuria, respectively. After 24 weeks, the placebo-adjusted mean change in HbA1c from baseline was -0.60% (-6.6 mmol/mol) (95% confidence interval [CI], -0.78 to -0.43 [-8.5 to -4.7 mmol/mol]; P <.0001). The placebo-adjusted gMean for time-weighted average of percentage change in UACR from baseline was -6.0% (95% CI, -15.0 to 3.0; P =.1954). The adverse-event profile, including renal safety and change in eGFR, was similar between the linagliptin and placebo groups. Conclusions: In individuals at early stages of diabetic kidney disease, linagliptin significantly improved glycaemic control but did not significantly lower albuminuria. There was no significant change in placebo-adjusted eGFR. Detection of clinically relevant renal effects of linagliptin may require longer treatment, as its main experimental effects in animal studies have been to reduce interstitial fibrosis rather than alter glomerular haemodynamics.