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  • 1
    Keywords: RECEPTOR ; EXPRESSION ; RISK ; CALCIUM ; inflammation ; METAANALYSIS ; GENOME-WIDE ASSOCIATION ; INSULIN-SECRETION ; VITAMIN-D SUPPLEMENTATION ; GLUCOSE-TOLERANCE
    Abstract: It is unclear whether vitamin D lowers risk of type 2 diabetes (T2D). In an observational study, we assessed the prospective association between plasma 25-hydroxyvitamin D (25(OH)D) and incident T2D, and evaluated whether it holds up for genetically determined elevated 25(OH)D. We used a case-cohort study nested within the German arm of the European Prospective Investigation into Cancer. From a total cohort of 53,088 participants with a mean follow-up of 6.6 years, we identified a random subcohort of 2,121 participants (57 % women) and 1,572 incident cases of T2D. 25(OH)D was measured in baseline plasma samples retrieved from frozen storage. Mean plasma 25(OH)D in the subcohort was 47.1 (5th-95th percentile 19.6-80.7) nmol/L. After controlling for age, sex, center, season of blood draw, education, and lifestyle, the hazard of T2D decreased across increasing plasma concentrations of 25(OH)D (P linear trend 〈 0.0001). The association became non-linear after adjustment for BMI and waist circumference (P non-linearity 〈 0.0001), with the inverse association being restricted to participants with 25(OH)D concentrations below similar to 45 nmol/L (hazard ratio per 5 nmol/L higher 25(OH)D 0.91, 95 % CI 0.84-0.98). A score predicting genetically determined plasma 25(OH)D by weighting four independent single-nucleotide polymorphisms by their effect on 25(OH)D, explained 3.7 % of the variance in 25(OH)D. The hazard ratio (95 % CI) per 5 nmol/L higher genetically predicted 25(OH)D was 0.98 (0.89-1.08) in the entire study sample and 1.06 (0.93-1.21) in the sub-sample with 25(OH)D 〈 45 nmol/L. This latter finding casts doubt on a strong causal association of 25(OH)D with T2D, but further research in large-scale consortia is needed.
    Type of Publication: Journal article published
    PubMed ID: 24002339
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  • 2
    Keywords: RECEPTOR ; EXPRESSION ; KINASE ; PROTEIN ; ACTIVATION ; GLYCATION END-PRODUCTS ; OXIDATIVE STRESS ; p38 ; METHYLGLYOXAL INDUCES APOPTOSIS ; GLYOXAL
    Abstract: Tamoxifen is the standard adjuvant endocrine therapy for estrogen-receptor positive premenopausal breast cancer patients. However, tamoxifen resistance is frequently observed under therapy. A tamoxifen resistant cell line has been generated from the estrogen receptor positive mamma carcinoma cell line MCF-7 and was analyzed for putative differences in the aldehyde defence system and accumulation of advanced glycation end products (AGE). In comparison to wt MCF-7 cells, these tamoxifen resistant cells were more sensitive to the dicarbonyl compounds glyoxal and methylglyoxal and displayed increased caspase activity, p38-MAPK- and I kappa B alpha-phosphorylation. However, mRNA accumulation of the aldehyde-and AGE-defence enzymes glyoxalase-1 and -2 (GLO1, GLO2) as well as fructosamine-3-kinase (FN3K) was not significantly altered. Tamoxifen resistant cells contained less free sulfhydryl-groups (glutathione) suggesting that the increased sensitivity towards the dicarbonyls was due to a higher sensitivity towards reactive oxygen species which are associated with dicarbonyl stress. To further analyse, if these data are of more general importance, key experiments were replicated with tamoxifen resistant MCF-7 cell lines from two independent sources. These cell lines were also more sensitive to aldehydes, especially glyoxal, but were different in their cellular signalling responses to the aldehydes. In conclusion, glyoxalases and other aldehyde defence enzymes might represent a promising target for the therapy of tamoxifen resistant breast cancers.
    Type of Publication: Journal article published
    PubMed ID: 24983248
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