A randomized trial of selenium supplementation and risk of type-2 diabetes, as assessed by plasma adiponectin

Background: Evidence that selenium affects the risk of type-2 diabetes is conflicting, with observational studies and a few randomized trials showing both lower and higher risk linked to the level of selenium intake and status. We investigated the effect of selenium supplementation on the risk of type-2 diabetes in a population of relatively low selenium status as part of the UK PRECISE (PREvention of Cancer by Intervention with SElenium) pilot study. Plasma adiponectin concentration, a recognised independent predictor of type-2 diabetes risk and known to be correlated with circulating selenoprotein P, was the biomarker chosen. Methods: In a randomized, double-blind, placebo-controlled trial, five hundred and one elderly volunteers were randomly assigned to a six-month intervention with 100, 200 or 300 μg selenium/d as high-selenium or placebo yeast. Adiponectin concentration was measured by ELISA at baseline and after six months of treatment in 473 participants with one or both plasma samples available. Results: Mean (SD) plasma selenium concentration was 88.5 ng/g (19.1) at baseline and increased significantly in the selenium-treatment groups. In baseline cross-sectional analyses, the fully adjusted geometric mean of plasma adiponectin was 14% lower (95% CI, 0-27%) in the highest than in the lowest quartile of plasma selenium (P for linear trend = 0.04). In analyses across randomized groups, however, selenium supplementation had no effect on adiponectin levels after six months of treatment (P = 0.96). Conclusions: These findings are reassuring as they did not show a diabetogenic effect of a six-month supplementation with selenium in this sample of elderly individuals of relatively low selenium status

Altered capacity for h 2 s production during the spontaneous differentiation of caco-2 cells to colonocytes due to reciprocal regulation of cbs and selenbp1

Hydrogen sulfide (H 2 S) has been proposed to promote tumor growth. Elevated H 2 S levels have been detected in human colorectal cancer (CRC) biopsies, resulting from the selective upregulation of cystathionine β-synthase (CBS). In contrast, the recently identified novel H 2 S-generating enzyme, selenium-binding protein 1 (SELENBP1), is largely suppressed in tumors. Here, we provide the first comparative analysis of the four human H 2 S-producing enzymes and the key H 2 S-catabolizing enzyme, sulfide:quinone oxidoreductase (SQOR), in Caco-2 human colorectal adenocarcinoma cells. The gene expression pattern of proliferating Caco-2 cells parallels that of CRC, while confluent cells undergo spontaneous differentiation to a colonocyte-like phenotype. SELENBP1 and SQOR were strongly upregulated during spontaneous differentiation, whereas CBS was downregulated. Cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase remained unaffected. Terminally differentiated cells showed an enhanced capacity to produce H 2 S from methanethiol and homocysteine. Differentiation induced by exposure to butyrate also resulted in the upregulation of SELENBP1, accompanied by increased SELENBP1 promoter activity. In contrast to spontaneous differentiation, however, butyrate did not cause downregulation of CBS. In summary, SELENBP1 and CBS are reciprocally regulated during the spontaneous differentiation of Caco-2 cells, thus paralleling their opposing regulation in CRC. Butyrate exposure, while imitating some aspects of spontaneous differentiation, does not elicit the same expression patterns of genes encoding H 2 S-modulating enzymes

High selenium intake and increased diabetes risk: experimental evidence for interplay between selenium and carbohydrate metabolism

The essential trace element selenium has long been considered to exhibit anti-diabetic and insulin-mimetic properties, but recent epidemiological studies indicated supranutritional selenium intake and high plasma selenium levels as possible risk factors for development of type 2 diabetes, pointing to adverse effects of selenium on carbohydrate metabolism in humans. However, increased plasma selenium levels might be both a consequence and a cause of diabetes. We summarize current evidence for an interference of selenium compounds with insulin-regulated molecular pathways, most notably the phosphoinositide-3-kinase/protein kinase B signaling cascade, which may underlie some of the pro- and anti-diabetic actions of selenium. Furthermore, we discuss reports of hyperinsulinemia, hyperglycemia and insulin resistance in mice overexpressing the selenoenzyme glutathione peroxidase 1. The peroxisomal proliferator-activated receptor gamma coactivator 1α represents a key regulator for biosynthesis of the physiological selenium transporter, selenoprotein P, as well as for hepatic gluconeogenesis. As proliferator-activated receptor gamma coactivator 1α has been shown to be up-regulated in livers of diabetic animals and to promote insulin resistance, we hypothesize that dysregulated pathways in carbohydrate metabolism and a disturbance of selenium homeostasis are linked via proliferator-activated receptor gamma coactivator 1α

Activation of Nrf2 by electrophiles is largely independent of the selenium status of HepG2 cells

Selenoenzymes, whose activity depends on adequate selenium (Se) supply, and phase II enzymes, encoded by target genes of nuclear factor erythroid 2-related factor 2 (Nrf2), take part in governing cellular redox homeostasis. Their interplay is still not entirely understood. Here, we exposed HepG2 hepatoma cells cultured under Se-deficient, Se-adequate, or Se-supranutritional conditions to the Nrf2 activators sulforaphane, cardamonin, or diethyl maleate. Nrf2 protein levels and intracellular localization were determined by immunoblotting, and mRNA levels of Nrf2 target genes and selenoproteins were assessed by qRT-PCR. Exposure to electrophiles resulted in rapid induction of Nrf2 and its enrichment in the nucleus, independent of the cellular Se status. All three electrophilic compounds caused an enhanced expression of Nrf2 target genes, although with differences regarding extent and time course of their induction. Whereas Se status did not significantly affect mRNA levels of the Nrf2 target genes, gene expression of selenoproteins with a low position in the cellular “selenoprotein hierarchy”, such as glutathione peroxidase 1 (GPX1) or selenoprotein W (SELENOW), was elevated under Se-supplemented conditions, as compared to cells held in Se-deficient media. In conclusion, no major effect of Se status on Nrf2 signalling was observed in HepG2 cells

SEMO ‐1, a novel methanethiol oxidase in Caenorhabditis elegans , is a pro‐aging factor conferring selective stress resistance

Methanethiol is a toxic gas produced through bacterial degradation of sulfur‐containing amino acids. Applying a novel enzymatic assay, we here identified a methanethiol oxidase (MTO) that catalyzes the degradation of methanethiol in the nematode Caenorhabditis elegans ( C. elegans ). The corresponding protein, Y37A1B.5, previously characterized as a C. elegans ortholog of human selenium‐binding protein 1 (SELENBP1), was renamed SEMO‐1 (SELENBP1 ortholog with methanethiol oxidase activity). Worms rendered deficient in SEMO‐1 not only showed decreased hydrogen sulfide production from methanethiol catabolism but they were also more resistant to oxidative stress and had an elevated life span. In contrast, resistance to selenite was significantly lowered in SEMO‐1‐deficient worms. Naturally occurring mutations of human SELENBP1 were introduced to recombinant SEMO‐1 through site‐directed mutagenesis and resulted in loss of its MTO activity, indicating a similar enzymatic mechanism for SELENBP1 and SEMO‐1. In summary, SEMO‐1 confers resistance to toxic selenite and the ability to metabolize toxic methanethiol. These beneficial effects might be a trade‐off for its negative impact on C. elegans life span

European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS).

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics briefly described below. The formation of reactive oxygen and nitrogen species (RONS) is an established hallmark of our aerobic environment and metabolism but RONS also act as messengers via redox regulation of essential cellular processes. The fact that many diseases have been found to be associated with oxidative stress established the theory of oxidative stress as a trigger of diseases that can be corrected by antioxidant therapy. However, while experimental studies support this thesis, clinical studies still generate controversial results, due to complex pathophysiology of oxidative stress in humans. For future improvement of antioxidant therapy and better understanding of redox-associated disease progression detailed knowledge on the sources and targets of RONS formation and discrimination of their detrimental or beneficial roles is required. In order to advance this important area of biology and medicine, highly synergistic approaches combining a variety of diverse and contrasting disciplines are needed.The EU-ROS consortium (COST Action BM1203) was supported by the European Cooperation in Science and Technology (COST). The present overview represents the final Action dissemination summarizing the major achievements of COST Action BM1203 (EU-ROS) as well as research news and personal views of its members. Some authors were also supported by COST Actions BM1005 (ENOG) and BM1307 (PROTEOSTASIS), as well as funding from the European Commission FP7 and H2020 programmes, and several national funding agencies

Krebsdiäten - vom Heilfasten zu Paläo - was ist davon zu halten?

Inhalt: Artikel in PubMed; Krebs und Ernährung; Aktuelle ACS Leitlinien zur Krebsprävention durch Ernährung; Diskutierte Ursachen der Assoziation von Diabetes und Krebs; DGE - Ernährungstipps für Krebskranke; Beispiele für "Krebsdiäten"; Erhöhte Aufnahme und Metabolisierung von Glucose in Tumorzellen; Diätarten - Auswirkungen und Risike

Cellular adaptation to xenobiotics: Interplay between xenosensors, reactive oxygen species and FOXO transcription factors

Cells adapt to an exposure to xenobiotics by upregulating the biosynthesis of proteins involved in xenobiotic metabolism. This is achieved largely via activation of cellular xenosensors that modulate gene expression. Biotransformation of xenobiotics frequently comes with the generation of reactive oxygen species (ROS). ROS, in turn, are known modulators of signal transduction processes. FOXO (forkhead box, class O) transcription factors are among the proteins deeply involved in the cellular response to stress, including oxidative stress elicited by the formation of ROS. On the one hand, FOXO activity is modulated by ROS, while on the other, FOXO target genes include many that encode antioxidant proteins – thereby establishing a regulatory circuit. Here, the role of ROS and of FOXOs in the regulation of xenosensor transcriptional activities will be discussed. Constitutive androstane receptor (CAR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), arylhydrocarbon receptor (AhR) and nuclear factor erythroid 2-related factor 2 (Nrf2) all interact with FOXOs and/or ROS. The two latter not only fine-tune the activities of xenosensors but also mediate interactions between them. As a consequence, the emerging picture of an interplay between xenosensors, ROS and FOXO transcription factors suggests a modulatory role of ROS and FOXOs in the cellular adaptive response to xenobiotics

The role of selenium in type-2 diabetes mellitus and its metabolic comorbidities

This narrative review addresses the role of the essential trace element, selenium, in type-2 diabetes mellitus (T2DM) and its metabolic co-morbidities, i.e., metabolic syndrome, obesity and non-alcoholic fatty liver disease. We refer to the dietary requirements of selenium and the key physiological roles of selenoproteins. We explore the dysregulated fuel metabolism in T2DM and its co-morbidities, emphasizing the relevance of inflammation and oxidative stress. We describe the epidemiology of observational and experimental studies of selenium in diabetes and related conditions, explaining that the interaction between selenium status and glucose control is not limited to hyperglycemia but extends to hypoglycemia. We propose that the association between high plasma/serum selenium and T2DM/fasting plasma glucose observed in many cross-sectional studies may rely on the upregulation of hepatic selenoprotein-P biosynthesis in conditions of hyperglycemia and insulin resistance. While animal studies have revealed potential molecular mechanisms underlying adverse effects of severe selenium/selenoprotein excess and deficiency in the pathogenesis of insulin resistance and β-cell dysfunction, their translational significance is rather limited. Importantly, dietary selenium supplementation does not appear to be a major causal factor for the development of T2DM in humans though we cannot currently exclude a small contribution of selenium on top of other risk factors, in particular if it is ingested at high (supranutritional) doses. Elevated selenium biomarkers that are often measured in T2DM patients are more likely to be a consequence, rather than a cause, of diabetes