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      Lifestyle and clinical determinants of skin autofluorescence in a population‐based cohort study

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          Abstract

          Background

          Skin autofluorescence ( SAF) is a noninvasive marker of advanced glycation end products ( AGEs). In diabetes, higher SAF levels have been positively associated with long‐term complications, cardiovascular morbidity and mortality. Because little is known about the factors that influence SAF in nondiabetic individuals, we assessed the association of clinical and lifestyle parameters with SAF as well as their interactions in a large‐scale, nondiabetic population and performed the same analysis in a type 2 diabetic subgroup.

          Methods

          In a cross‐sectional study in participants from the LifeLines Cohort Study, extensive clinical and biochemical phenotyping, including SAF measurement, was assessed in 9009 subjects of whom 314 (3·5%) subjects with type 2 diabetes.

          Results

          Mean SAF was 2·04 ± 0·44 arbitrary units ( AU) in nondiabetic individuals and 2·44 ± 0·55 AU in type 2 diabetic subjects ( P < 0·0001). Multivariate backward regression analysis showed that in the nondiabetic population, SAF was significantly and independently associated with age, BMI, HbA1c, creatinine clearance, genetic polymorphism in NAT2 (rs4921914), current smoking, pack‐years of smoking and coffee consumption. In the type 2 diabetic group, a similar set of factors was associated with SAF, except for coffee consumption.

          Conclusions

          In addition to the established literature on type 2 diabetes, we have demonstrated that SAF levels are associated with several clinical and lifestyle factors in the nondiabetic population. These parameters should be taken into consideration when using SAF as a screening or prediction tool for populations at risk for cardiovascular disease and diabetes.

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          Most cited references34

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          Prediction of creatinine clearance from serum creatinine.

          A formula has been developed to predict creatinine clearance (Ccr) from serum creatinine (Scr) in adult males: (see article)(15% less in females). Derivation included the relationship found between age and 24-hour creatinine excretion/kg in 249 patients aged 18-92. Values for Ccr were predicted by this formula and four other methods and the results compared with the means of two 24-hour Ccr's measured in 236 patients. The above formula gave a correlation coefficient between predicted and mean measured Ccr's of 0.83; on average, the difference predicted and mean measured values was no greater than that between paired clearances. Factors for age and body weight must be included for reasonable prediction.
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            Effect of collagen turnover on the accumulation of advanced glycation end products.

            Collagen molecules in articular cartilage have an exceptionally long lifetime, which makes them susceptible to the accumulation of advanced glycation end products (AGEs). In fact, in comparison to other collagen-rich tissues, articular cartilage contains relatively high amounts of the AGE pentosidine. To test the hypothesis that this higher AGE accumulation is primarily the result of the slow turnover of cartilage collagen, AGE levels in cartilage and skin collagen were compared with the degree of racemization of aspartic acid (% d-Asp, a measure of the residence time of a protein). AGE (N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, and pentosidine) and % d-Asp concentrations increased linearly with age in both cartilage and skin collagen (p < 0.0001). The rate of increase in AGEs was greater in cartilage collagen than in skin collagen (p < 0.0001). % d-Asp was also higher in cartilage collagen than in skin collagen (p < 0.0001), indicating that cartilage collagen has a longer residence time in the tissue, and thus a slower turnover, than skin collagen. In both types of collagen, AGE concentrations increased linearly with % d-Asp (p < 0.0005). Interestingly, the slopes of the curves of AGEs versus % d-Asp, i.e. the rates of accumulation of AGEs corrected for turnover, were identical for cartilage and skin collagen. The present study thus provides the first experimental evidence that protein turnover is a major determinant in AGE accumulation in different collagen types. From the age-related increases in % d-Asp the half-life of cartilage collagen was calculated to be 117 years and that of skin collagen 15 years, thereby providing the first reasonable estimates of the half-lives of these collagens.
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              Tobacco smoke is a source of toxic reactive glycation products.

              Smokers have a significantly higher risk for developing coronary and cerebrovascular disease than nonsmokers. Advanced glycation end products (AGEs) are reactive, cross-linking moieties that form from the reaction of reducing sugars and the amino groups of proteins, lipids, and nucleic acids. AGEs circulate in high concentrations in the plasma of patients with diabetes or renal insufficiency and have been linked to the accelerated vasculopathy seen in patients with these diseases. Because the curing of tobacco takes place under conditions that could lead to the formation of glycation products, we examined whether tobacco and tobacco smoke could generate these reactive species that would increase AGE formation in vivo. Our findings show that reactive glycation products are present in aqueous extracts of tobacco and in tobacco smoke in a form that can rapidly react with proteins to form AGEs. This reaction can be inhibited by aminoguanidine, a known inhibitor of AGE formation. We have named these glycation products "glycotoxins." Like other known reducing sugars and reactive glycation products, glycotoxins form smoke, react with protein, exhibit a specific fluorescence when cross-linked to proteins, and are mutagenic. Glycotoxins are transferred to the serum proteins of human smokers. AGE-apolipoprotein B and serum AGE levels in cigarette smokers were significantly higher than those in nonsmokers. These results suggest that increased glycotoxin exposure may contribute to the increased incidence of atherosclerosis and high prevalence of cancer in smokers.
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                Author and article information

                Journal
                Eur J Clin Invest
                Eur. J. Clin. Invest
                10.1111/(ISSN)1365-2362
                ECI
                European Journal of Clinical Investigation
                John Wiley and Sons Inc. (Hoboken )
                0014-2972
                1365-2362
                15 April 2016
                May 2016
                : 46
                : 5 ( doiID: 10.1111/eci.2016.46.issue-5 )
                : 481-490
                Affiliations
                [ 1 ] Department of Endocrinology University of GroningenUniversity Medical Center Groningen GroningenThe Netherlands
                [ 2 ] Program in Genetics and Genome BiologyHospital for Sick Children Toronto ONCanada
                Author notes
                [*] [* ] Correspondence to: Robert P. van Waateringe, MD, Department of Endocrinology, University of Groningen, University Medical Center Groningen, HPC AA31, P.O. Box 30001, 9700 RB Groningen, The Netherlands. Tel.: +31 50 3612978; fax: +31 50 3619392; e‐mail: r.p.van.waateringe@ 123456umcg.nl
                Article
                ECI12627
                10.1111/eci.12627
                5111733
                27002914
                cfd6d1c9-9fb1-4029-aa10-13a13d10b8fb
                © 2016 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 28 September 2015
                : 18 March 2016
                Page count
                Pages: 10
                Funding
                Funded by: Netherlands Consortium for Healthy Ageing (NCHA)
                Funded by: Biobank Standardisation and Harmonization for Research Excellence in the European Union (Bio‐SHaRE‐EU)
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                eci12627
                May 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.7 mode:remove_FC converted:16.11.2016

                Medicine
                advanced glycation end products,aging,cardiovascular disease,determinants,skin autofluorescence,type 2 diabetes

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