| 1. |
- Aglago, Elom K., et al.
(författare)
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Dietary Advanced Glycation End-Products and Colorectal Cancer Risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study
- 2021
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Ingår i: Nutrients. - : MDPI. - 2072-6643. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- Dietary advanced glycation end-products (dAGEs) have been hypothesized to be associated with a higher risk of colorectal cancer (CRC) by promoting inflammation, metabolic dysfunction, and oxidative stress in the colonic epithelium. However, evidence from prospective cohort studies is scarce and inconclusive. We evaluated CRC risk associated with the intake of dAGEs in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Dietary intakes of three major dAGEs: Nε-carboxy-methyllysine (CML), Nε-carboxyethyllysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated in 450,111 participants (median follow-up = 13 years, with 6162 CRC cases) by matching to a detailed published European food composition database. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of dAGEs with CRC were computed using multivariable-adjusted Cox regression models. Inverse CRC risk associations were observed for CML (HR comparing extreme quintiles: HRQ5vs.Q1 = 0.92, 95% CI = 0.85-1.00) and MG-H1 (HRQ5vs.Q1 = 0.92, 95% CI = 0.85-1.00), but not for CEL (HRQ5vs.Q1 = 0.97, 95% CI = 0.89-1.05). The associations did not differ by sex or anatomical location of the tumor. Contrary to the initial hypothesis, our findings suggest an inverse association between dAGEs and CRC risk. More research is required to verify these findings and better differentiate the role of dAGEs from that of endogenously produced AGEs and their precursor compounds in CRC development.
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| 2. |
- Hop, Paul J., et al.
(författare)
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Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
- 2022
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 14:633
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Tidskriftsartikel (refereegranskat)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.
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| 3. |
- Roest, Pauline A.M., et al.
(författare)
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Specific Local Cardiovascular Changes of N-epsilon-(Carboxymethyl)lysine, Vascular Endothelial Growth Factor, and Smad2 in the Developing Embryos Coincide With Maternal Diabetes-Induced Congenital Heart Defects
- 2009
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 58:5, s. 1222-1228
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Embryos exposed to a diabetic environment in utero have an increased risk to develop congenital heart malformations. The mechanism behind the teratogenicity of diabetes still remains enigmatic. Detrimental effects of glycation products in diabetic patients have been well documented. We therefore studied a possible link between glycation products and the development of congenital cardiovascular malformations. Furthermore, we investigated other possible mechanisms involved in this pathogenesis: alterations in the levels of vascular endothelial growth factor (VEGF) or phosphorylated Smad2 (the latter can be induced by both glycation products and VEGF). RESEARCH DESIGN AND METHODS: We examined the temporal spatial patterning of the glycation products Nepsilon(carboxymethyl)lysine (CML) and methylglyoxal (MG) adducts, VEGF expression, and phosphorylated Smad2 during cardiovascular development in embryos from normal and diabetic rats. RESULTS: Maternal diabetes increased the CML accumulation in the areas susceptible to diabetes-induced congenital heart disease, including the outflow tract of the heart and the aortic arch. No MG adducts could be detected, suggesting that CML is more likely to be indicative for increased oxidative stress than for glycation. An increase of CML in the outflow tract of the heart was accompanied by an increase in phosphorylated Smad2, unrelated to VEGF. VEGF showed a time-specific decrease in the outflow tract of embryos from diabetic dams. CONCLUSIONS: From our results, we can conclude that maternal diabetes results in transient and localized alterations in CML, VEGF expression, and Smad2 phosphorylation overlapping with those regions of the developing heart that are most sensitive to diabetes-induced congenital heart disease.
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| 4. |
- Aglago, Elom K., et al.
(författare)
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Soluble Receptor for Advanced Glycation End-products (sRAGE) and Colorectal Cancer Risk : A Case-Control Study Nested within a European Prospective Cohort
- 2021
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 30:1, s. 182-192
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Overexpression of the receptor for advanced glycation end-product (RAGE) has been associated with chronic inflammation, which in turn has been associated with increased colorectal cancer risk. Soluble RAGE (sRAGE) competes with RAGE to bind its ligands, thus potentially preventing RAGE-induced inflammation.METHODS: To investigate whether sRAGE and related genetic variants are associated with colorectal cancer risk, we conducted a nested case-control study in the European Prospective Investigation into Cancer and Nutrition (EPIC). Plasma sRAGE concentrations were measured by ELISA in 1,361 colorectal cancer matched case-control sets. Twenty-four SNPs encoded in the genes associated with sRAGE concentrations were available for 1,985 colorectal cancer cases and 2,220 controls. Multivariable adjusted ORs and 95% confidence intervals (CIs) were computed using conditional and unconditional logistic regression for colorectal cancer risk and circulating sRAGE and SNPs, respectively.RESULTS: Higher sRAGE concentrations were inversely associated with colorectal cancer (ORQ5vs.Q1, 0.77; 95% CI, 0.59-1.00). Sex-specific analyses revealed that the observed inverse risk association was restricted to men (ORQ5vs.Q1, 0.63; 95% CI, 0.42-0.94), whereas no association was observed in women (ORQ5vs.Q1, 1.00; 95% CI, 0.68-1.48; Pheterogeneity for sex = 0.006). Participants carrying minor allele of rs653765 (promoter region of ADAM10) had lower colorectal cancer risk (C vs. T, OR, 0.90; 95% CI, 0.82-0.99).CONCLUSIONS: Prediagnostic sRAGE concentrations were inversely associated with colorectal cancer risk in men, but not in women. An SNP located within ADAM10 gene, pertaining to RAGE shedding, was associated with colorectal cancer risk.IMPACT: Further studies are needed to confirm our observed sex difference in the association and better explore the potential involvement of genetic variants of sRAGE in colorectal cancer development.
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| 5. |
- Debras, Charlotte, et al.
(författare)
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Dietary intake of dicarbonyl compounds and changes in body weight over time in a large cohort of European adults
- 2024
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Ingår i: British Journal of Nutrition. - : Cambridge University Press. - 0007-1145 .- 1475-2662. ; 131:11, s. 1902-1914
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Tidskriftsartikel (refereegranskat)abstract
- Dicarbonyl compounds are highly reactive precursors of Advanced Glycation End-products (AGEs), produced endogenously, present in certain foods, and formed during food processing. AGEs contribute to development of adverse metabolic outcomes but health effects of dietary dicarbonyls are largely unexplored. We investigated associations between three dietary dicarbonyl compounds, methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG), and body-weight changes in European adults. Dicarbonyl intakes were estimated using food composition database from 263,095 EPIC-PANACEA participants with two body-weight assessments (median follow-up time=5.4y). Associations between dicarbonyls and 5-year body-weight changes were estimated using mixed linear regression models. Stratified analyses by sex, age, and baseline BMI were performed. Risk of becoming overweight/obese was assessed using multivariable-adjusted logistic regression. MGO intake was associated with 5-year body-weight gain of 0.089kg (per 1-SD increase, 95%CI=0.072, 0.107). 3-DG was inversely associated with body-weight change (-0.076kg, -0.094, -0.058). No significant association was observed for GO (0.018kg, -0.002, 0.037). In stratified analyses, GO was associated with body-weight gain among women and older participants (above median of 52.4y). MGO was associated with higher body-weight gain among older participants. 3-DG was inversely associated with body-weight gain among younger and normal-weight participants. MGO was associated with higher risk of becoming overweight/obese, while inverse associations were observed for 3-DG. No associations were observed for GO with overweight/obesity. Dietary dicarbonyls are inconsistently associated with body-weight change among European adults. Further research is needed to clarify the role of these food components in overweight and obesity, their underlying mechanisms, and potential public-health implications.
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| 6. |
- Engelen, Lian, et al.
(författare)
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Improved glycemic control induced by both metformin and repaglinide is associated with a reduction in blood levels of 3-deoxyglucosone in nonobese patients with type 2 diabetes
- 2011
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Ingår i: European Journal of Endocrinology. - 1479-683X. ; 164:3, s. 371-379
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Metformin has been reported to reduce alpha-dicarbonyls, which are known to contribute to diabetic complications. It is unclear whether this is due to direct quenching of alpha-dicarbonyls or to an improvement in glycemic control. We therefore compared the effects of metformin versus repaglinide, an antihyperglycemic agent with an insulin-secreting mechanism, on the levels of the alpha-dicarbonyl 3-deoxyglucosone (3DG). Methods: We conducted a single-center, double-masked, double-dummy, crossover study involving 96 nonobese patients with type 2 diabetes. After a 1-month run-in on diet-only treatment, patients were randomized to either repaglinide (6 mg daily) followed by metformin (2 g daily) or vice versa each during 4 months with a 1-month washout between interventions. Results: 3DG levels decreased after both metformin (-19.3% (95% confidence interval (CI): -23.5, -14.8)) and repaglinide (-20.8% (95% CI: -24.9, -16.3)) treatments, but no difference was found between treatments (1.8% (95% CI: -3.8, 7.8)). Regardless of the treatment, changes in glycemic variables were associated with changes in 3DG. Specifically, 3DG decreased by 22.7% (95% CI: 19.0, 26.5) per S. D. decrease in fasting plasma glucose (PG), by 20.0% (95% CI: 16.2, 23.9) per S. D. decrease in seven-point mean plasma glucose, by 22.5% (95% CI: 18.6, 26.6) per S. D. decrease in area under the curve for PG, by 17.2% (95% CI: 13.8, 20.6) per S. D. decrease in HbAlc, and by 10.9% (95% CI: 6.4, 15.5) per S. D. decrease in Amadori albumin. In addition, decreases in 3DG were associated with decreases in advanced glycation endproducts and endothelial markers. Conclusion: Improved glycemic control induced by both metformin and repaglinide is associated with a reduction in 3DG levels in nonobese individuals with type 2 diabetes. This may constitute a shared metabolic pathway through which both treatments have a beneficial impact on the cardiovascular risk.
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| 7. |
- Lund, Soren S, et al.
(författare)
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Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes
- 2008
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Ingår i: European Journal of Endocrinology. - 1479-683X. ; 158:5, s. 631-641
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Tidskriftsartikel (refereegranskat)abstract
- Objective: In patients with type 2 diabetes mellitus (T2DM), biomarkers reflecting inflammation and endothelial dysfunction have been linked to cardiovascular disease (CVD biomarkers) and metabolic regulation. In T2DM patients, metformin and insulin secretagogues have demonstrated equal anti-hyperglycaemic potency. Here, we report the effect of metformin versus an insulin secretagogue, repaglinide, on CVD biomarkers in non-obese T2DM patients. Design and methods: Single-centre, double-masked, double-dummy, crossover study during 2x4 months involving 96 non-obese (body mass index <= 27kg/m(2)) insulin-naive T2DM patients. At enrolment, previous oral hypoglycaemic agents were stopped and the patients entered a 1-month run- on diet-only treatment. Hereafter, patients were randomized to either 2 mg repaglinide thrice daily followed by 1 g metformin twice daily or vice versa each during 4 months with a 1-month washout between interventions. Results: Levels of tumour necrosis factor-alpha, plasminogen activator inhibitor-1 antigen, tissue-type plasminogen activator antigen, von Willebrand factor, soluble intercellular adhesion molecule-1 and soluble E-selectin were significantly lower during metformin versus repaglinide treatments. In contrast, Amadori albumin and heart rate were higher during metformin versus repaglinide. Levels of interleukin-6. fibrinogen, soluble vascular cell adhesion molecule-1, asymmetric dimethylarginine and advanced glycation end products as well as glycaemic levels (previously reported) and 24-h blood pressure were similar between treatments. Adjustment for known macrovascular disease did not affect the between-treatment: effects. Conclusions: In non-obese T2DM patients, metformin was more effective in reducing selected biomarkers reflecting inflammation and endothelial dysfunction compared with repaglinide despite similar glycaemic levels between treatments.
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| 8. |
- Mayén, Ana-Lucia, et al.
(författare)
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Dietary intake of advanced glycation endproducts and risk of hepatobiliary cancers : a multinational cohort study
- 2021
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 149:4, s. 854-864
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Tidskriftsartikel (refereegranskat)abstract
- Advanced glycation endproducts (AGEs) may contribute to liver carcinogenesis because of their pro-inflammatory and pro-oxidative properties. Diet is a major source of AGEs, but there is sparse human evidence on the role of AGEs intake in liver cancer aetiology. We examined the association between dietary AGEs and the risk of hepatobiliary cancers in the European Prospective Investigation into Cancer and Nutrition prospective cohort (n=450,111). Dietary intake of three AGEs, Nε -[carboxymethyl]lysine (CML), Nε -[1-carboxyethyl]lysine (CEL), and Nδ -[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), was estimated using country-specific dietary questionnaires linked to an AGEs database. Cause-specific hazard ratios (HR) and their 95% confidence intervals (CI) for associations between dietary AGEs and risk of hepatocellular carcinoma (HCC), gallbladder, and biliary tract cancers were estimated using multivariable Cox proportional hazard regression. After a median follow-up time of 14.9 years, 255 cases of HCC, 100 cases of gallbladder cancer, and 173 biliary tract cancers were ascertained. Higher intakes of dietary AGEs were inversely associated with risk of HCC (per 1 standard deviation [SD] increment, HR-CML =0.87, 95% CI: 0.76 to 0.99, HR-CEL =0.84, 95% CI: 0.74 to 0.96, and HR-MH-G1 = 0.84, 95% CI: 0.74 to 0.97). In contrast, positive associations were observed with risk of gallbladder cancer (per 1 SD, HR-CML =1.28, 95% CI: 1.05 to 1.56, HR-CEL =1.17; 95% CI: 0.96 to 1.40, HR-MH-G1 =1.27, 95% CI: 1.06 to 1.54). No associations were observed for cancers of the intra- and extra-hepatic bile ducts. Our findings suggest that higher intakes of dietary AGEs are inversely associated with the risk of HCC and positively associated with the risk of gallbladder cancer.
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