Highlights Skin autofluorescence (SAF) assesses subcutaneous accumulation of advanced glycation end products and has been shown to predict future cardiovascular disease and diabetes. A higher number of pregnancies was significantly associated with higher SAF, even after correction for relevant confounders like waist circumference, creatinine clearance, and diabetes status, but not after correction for age. Women with the highest SAF Z-score had a more unfavorable risk factor profile, with higher body mass index and waist circumference, higher blood pressure, lower high-density lipoprotein cholesterol, and higher triglyceride levels

Ahmed

Blaauw

Coffeng

De Ranitz-Greven

Jacobs

Meerwaldt

Parikh

Toescu

HighlightsSkin autofluorescence (SAF) assesses subcutaneous accumulation of advanced glycation end products and has been shown to predict future cardiovascular disease and diabetes.A higher number of pregnancies was significantly associated with higher SAF, even after correction for relevant confounders like waist circumference, creatinine clearance, and diabetes status, but not after correction for age.Women with the highest SAF Z-score had a more unfavorable risk factor profile, with higher body mass index and waist circumference, higher blood pressure, lower high-density lipoprotein cholesterol, and higher triglyceride levels.</p

Van Waateringe, Robert P.

Truyens, Laura

Van Den Berg, Paul P.

Lutgers, Helen L.

Wolffenbuttel, Bruce H. R.

ARTS repository - University of Groningen

   University of GroningenSkin autofluorescence, a non-invasive biomarker for advanced glycation end products, is notrelated to the number of pregnanciesVan Waateringe, Robert P.; Truyens, Laura; Van Den Berg, Paul P.; Lutgers, Helen L.;Wolffenbuttel, Bruce H. R.Published in:Journal of diabetesDOI:10.1111/1753-0407.12782IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2018Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Van Waateringe, R. P., Truyens, L., Van Den Berg, P. P., Lutgers, H. L., & Wolffenbuttel, B. H. R. (2018).Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is not related to thenumber of pregnancies. Journal of diabetes, 10(11), 899-901. https://doi.org/10.1111/1753-0407.12782CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.RESEARCH LETTERSkin autofluorescence, a non-invasive biomarker foradvanced glycation end products, is not related to thenumber of pregnanciesRobert P. VAN WAATERINGE,1 Laura TRUYENS,2 Paul P. VAN DEN BERG,3 Helen L. LUTGERS4 andBruce H.R. WOLFFENBUTTEL 11Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, 2University ofLouvain, Louvain, Belgium, 3Department of Gynecology, University of Groningen, University Medical Center Groningen, Groningen, TheNetherlands, and 4Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, The NetherlandsKeywords: aging, diabetes, epidemiology, pregnancy, skin autofluorescence.To the EditorThe role of advanced glycation end products (AGEs)in the pathophysiology of diabetes-related complica-tions and aging has been studied extensively. The AGEsrepresent chronic exposure to hyperglycemia and oxida-tive stress. Tissue AGE accumulation can be assessednon-invasively by measuring skin autofluorescence(SAF) with a so-called AGE reader. Markers of oxida-tive stress are elevated during pregnancy, which can, inturn, increase the formation of AGEs.1 One studyreported that SAF levels were higher in pregnantwomen with pre-existing diabetes than in women withgestational diabetes and women without diabetes.2Preliminary data from our group suggested that SAFincreases during pregnancy and does not return to pre-pregnancy levels (B. Groen et al., unpublished data,2014). This phenomenon may be caused by increasedoxidative and glycemic stress during pregnancy. There-fore, the aim of the present study was to assess the rela-tionship between SAF and the number of pregnancies.MethodsSubjects included in the study were participants from theLifelines Cohort Study, a large population-based cohortstudy in the northern region of the Netherlands (www.lifelines.net, accessed 24 December 2017). The Lifelinesstudy was approved by the Medical Ethics Committee ofthe University Medical Center Groningen. Writteninformed consent was obtained from all participants.The present study included women of Western Europeandescent aged between 18 and 80 years for whom an SAFmeasurement was available. Subjects with type 1 andtype 2 diabetes were excluded, as were as those withmissing data for diabetes, leaving 47 834 individuals foranalysis. Subjects completed a questionnaire on medicalhistory, past and current diseases, use of medication, andhealth behavior. The questionnaire also included infor-mation on previous pregnancies and childbirth. Womenwere asked how many times they had been pregnant andhow many children were born. In the present study, SAFwas calculated as the mean of three consecutivemeasurements using an AGE Reader (DiagnOpticsCorrespondenceBruce H.R. Wolffenbuttel, Department of Endocrinology, UniversityMedical Center Groningen, HPC AA31, P.O. Box 30001, 9700 RBGroningen, The Netherlands.Tel: +31 50 3613962Fax: +31 50 3619392Email: bwo@umcg.nlReceived 25 December 2017; revised 20 April 2018; accepted 15May 2018doi: 10.1111/1753-0407.12782Highlights• Skin autofluorescence (SAF) assesses subcutaneous accumulation of advanced glycation end products and hasbeen shown to predict future cardiovascular disease and diabetes.• A higher number of pregnancies was significantly associated with higher SAF, even after correction for relevantconfounders like waist circumference, creatinine clearance, and diabetes status, but not after correction for age.• Women with the highest SAF Z-score had a more unfavorable risk factor profile, with higher body mass indexand waist circumference, higher blood pressure, lower high-density lipoprotein cholesterol, and higher triglycer-ide levels.Journal of Diabetes 10 (2018), 899–901© 2018 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,provided the original work is properly cited.899Technologies, Groningen, Netherlands).3 Age-adjustedSAF (Z-scores) was calculated because SAF is stronglyaffected by aging.3Data are given as the mean SD or as the median withinterquartile range (IQR) in the case of non-normallydistributed data. Linear regression analysis was per-formed to examine the association between the numberof pregnancies and SAF. In the multivariate models, weadjusted for relevant factors, such as waist circumference,body mass index (BMI), renal function, and smoking.Two-tailed P < 0.001 was considered significant.ResultsThe clinical characteristics of the study population aregiven in Table S1, available as Supplementary Materialto this paper. Mean subject age was 44 12 years,mean waist circumference was 87 12 cm, and meanBMI was 25.8 4.6 kg/m2. The median number ofpregnancies was 2.0 (IQR 1.0–3.0). In total, 20.5% ofwomen had not been pregnant, 42% reported one totwo pregnancies, 30% reported three to four pregnan-cies, and 7.5% reported five or more pregnancies. Ahigher number of pregnancies was associated withhigher SAF, which persisted after correction for waistcircumference and renal function (P < 0.0001). How-ever, after further correction for age, SAF was no lon-ger associated with the number of pregnancies(P = 0.713; Table 1). Fig. 1 shows that SAF Z-scoresare comparable in the various groups of women dividedaccording to the number of pregnancies. Women in thehighest quartile of the SAF Z-score had a higher preva-lence of metabolic syndrome, as well as higher BMI,waist circumference, glucose, HbA1c, and lipids (allP < 0.01) than women in the other three quartiles, anda similar number of pregnancies compared with thosein the lowest quartile (Table S2).DiscussionAfter correction for important confounders, SAFincreased with the number of pregnancies in womenfrom the general population. However, after correctionfor age, this association was no longer significant. Theincreased oxidative stress that occurs during pregnancymay significantly affect SAF measurements. Indeed, ithas been reported that SAF is elevated in women withpre-eclampsia and associated with increased carotidartery intima–media thickness, a marker for atheroscle-rosis.4 Moreover, SAF was associated with higherblood pressure, triglycerides, and C-reactive proteinlevels, indicating the potential cardiovascular risk asso-ciated with these factors.5 Therefore, we postulate thatthe effect of pregnancy on SAF may only be restrictedto pathological pregnancies, such as those complicatedby pre-eclampsia.4,5 Unfortunately, the Lifelines datasetdid not record any complications of pregnancy.Two important studies have reported on the associa-tion between reproductive history and cardiovascularhealth. One of these studies reported that a higher num-ber of pregnancies was associated with lower cardiovascu-lar mortality,6 whereas the other study showed that theTable 1 Univariate and multivariate analyses for skinautofluorescenceModel Parameters β P-value R2 (%)1 No. pregnancies 0.061 <0.0001 5.32 No. pregnancies 0.0003 0.800 30.7Age 0.020 <0.00013 No. pregnancies 0.0031 <0.0001 19.7Waist 0.013 <0.0001GFR −0.006 <0.00014 No. pregnancies 0.030 <0.0001 20.5Waist 0.012 <0.0001GFR −0.006 <0.0001Diabetes or glucose 0.084 <0.00015 No. pregnancies −0.0001 0.941 31.3Age 0.17 <0.0001Waist 0.004 <0.0001GFR −0.001 <0.0001Diabetes 0.015 <0.0001GFR, glomerular filtration rate.4.03.02.01.00.0-1.0SAF (Z-score)-2.0-3.0-4.00 1–2 3–4No. pregnancies 5–6 ≥7Figure 1 Number of pregnancies and age-corrected skin autofluor-escence (SAF) Z-score. The boxes show the interquartile range, withthe median value indicated by the horizontal line; whiskers showthe range. Dots indicate outliers.900 © 2018 The Authors.Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.Research Letter R.P. VAN WAATERINGE et al.number of pregnancies or live births was associated withhigher left ventricular mass and end-systolic volume.7 Arecent review suggested that pre-eclampsia is an under-recognized risk factor for ischemic heart disease, chronichypertension, peripheral vascular disease, and stroke.8In conclusion, in the present study SAF increasedwith a higher number of pregnancies, but not aftercorrection for participants’ age. Those with the highestage-corrected SAF had a worse risk factor profile forfuture cardiovascular disease.AcknowledgementsThe authors acknowledge all the participants of the Life-lines Cohort Study and everybody involved in the set-upand implementation of the study. Lifelines has beenfunded by a number of public sources, notably the DutchGovernment, The Netherlands Organization of ScientificResearch NWO (Grant 175.010.2007.006), the NorthernNetherlands Collaboration of Provinces (SNN), theEuropean Fund for Regional Development, Dutch Minis-try of Economic Affairs, Pieken in de Delta, Provinces ofGroningen and Drenthe, the Target project, BBMRI-NL(Biobanking and BioMolecular resources Research Infra-structure The Netherlands), the University of Groningen,and the University Medical Center Groningen. This workwas supported by the National Consortium for HealthyAgeing, and funds from the European Union’s SeventhFramework Program (FP7/2007–2013) through the Bio-bank Standardisation and Harmonisation for ResearchExcellence in the European Union (BioSHaRE-EU) pro-ject (Grant agreement 261433). Lifelines (BRIF4568) isengaged in a Bioresource research impact factor (BRIF)policy pilot study, details of which can be found at:https://www.bioshare.eu/content/bioresource-impact-factor(accessed 24 December 2017).DisclosureNone declared.References1. Toescu V, Nuttall SL, Martin U, Kendall MJ, Dunne F.Oxidative stress and normal pregnancy. Clin Endocrinol(Oxf ). 2002; 57: 609–13.2. De Ranitz-Greven WL, Kaasenbrood L, Poucki WKet al. Advanced glycation end products, measured as skinautofluorescence, during normal pregnancy and preg-nancy complicated by diabetes mellitus. Diabetes TechnolTher. 2012; 14: 1134–9.3. Meerwaldt R, Graaff R, Oomen PHN et al. Simple non-invasive assessment of advanced glycation endproductaccumulation. Diabetologia. 2004; 47: 1324–30.4. Blaauw J, Smit AJ, van Pampus MG et al. Skin auto-fluorescence, a marker of advanced glycation end prod-ucts and oxidative stress, is increased in recentlypreeclamptic women. Am J Obstet Gynecol. 2006; 195:717–22.5. Coffeng SM, Blaauw J, Souwer ET et al. Skin autofluor-escence as marker of tissue advanced glycation end-products accumulation in formerly preeclamptic women.Hypertens Pregnancy. 2011; 30: 231–42.6. Jacobs MB, Kritz-Silverstein D, Wingard DL, Barrett-Connor E. The association of reproductive history withall-cause and cardiovascular mortality in older women:The Rancho Bernardo Study. Fertil Steril. 2012; 97:118–24.7. Parikh NI, Lloyd-Jones DM, Ning H et al. Association ofnumber of live births with left ventricular structure andfunction. The Multi-Ethnic Study of Atherosclerosis(MESA). Am Heart J. 2012; 163: 470–6.8. Ahmed R, Dunford J, Mehran R, Robson S,Kunadian V. Pre-eclampsia and future cardiovascular riskamong women a review. J Am Coll Cardiol. 2014; 63:1815–22.Supporting informationAdditional supporting information may be found online inthe Supporting Information section at the end of thearticle:Table S1. Baseline characteristics of the participatingwomen.Table S2. Skin autofluorescence Z-scores and cardiovascu-lar risk factors.© 2018 The Authors.Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.901R.P. VAN WAATERINGE et al. Research Letter

English

Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is not related to the number of pregnancies

Robert P. Van Waateringe

Laura Truyens

Paul P. Van Den Berg

Helen L. Lutgers

Bruce H.R. Wolffenbuttel

Crossref

Journal of Diabetes

University of GroningenSkin autofluorescence, a non-invasive biomarker for advanced glycation end products, is notrelated to the number of pregnanciesVan Waateringe, Robert P.; Truyens, Laura; Van Den Berg, Paul P.; Lutgers, Helen L.;Wolffenbuttel, Bruce H. R.Published in:Journal of diabetesDOI:10.1111/1753-0407.12782IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2018Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Van Waateringe, R. P., Truyens, L., Van Den Berg, P. P., Lutgers, H. L., & Wolffenbuttel, B. H. R. (2018).Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is not related to thenumber of pregnancies. Journal of diabetes, 10(11), 899-901. https://doi.org/10.1111/1753-0407.12782CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 23-12-2025RESEARCH LETTERSkin autofluorescence, a non-invasive biomarker foradvanced glycation end products, is not related to thenumber of pregnanciesRobert P. VAN WAATERINGE,1 Laura TRUYENS,2 Paul P. VAN DEN BERG,3 Helen L. LUTGERS4 andBruce H.R. WOLFFENBUTTEL 11Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, 2University ofLouvain, Louvain, Belgium, 3Department of Gynecology, University of Groningen, University Medical Center Groningen, Groningen, TheNetherlands, and 4Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, The NetherlandsKeywords: aging, diabetes, epidemiology, pregnancy, skin autofluorescence.To the EditorThe role of advanced glycation end products (AGEs)in the pathophysiology of diabetes-related complica-tions and aging has been studied extensively. The AGEsrepresent chronic exposure to hyperglycemia and oxida-tive stress. Tissue AGE accumulation can be assessednon-invasively by measuring skin autofluorescence(SAF) with a so-called AGE reader. Markers of oxida-tive stress are elevated during pregnancy, which can, inturn, increase the formation of AGEs.1 One studyreported that SAF levels were higher in pregnantwomen with pre-existing diabetes than in women withgestational diabetes and women without diabetes.2Preliminary data from our group suggested that SAFincreases during pregnancy and does not return to pre-pregnancy levels (B. Groen et al., unpublished data,2014). This phenomenon may be caused by increasedoxidative and glycemic stress during pregnancy. There-fore, the aim of the present study was to assess the rela-tionship between SAF and the number of pregnancies.MethodsSubjects included in the study were participants from theLifelines Cohort Study, a large population-based cohortstudy in the northern region of the Netherlands (www.lifelines.net, accessed 24 December 2017). The Lifelinesstudy was approved by the Medical Ethics Committee ofthe University Medical Center Groningen. Writteninformed consent was obtained from all participants.The present study included women of Western Europeandescent aged between 18 and 80 years for whom an SAFmeasurement was available. Subjects with type 1 andtype 2 diabetes were excluded, as were as those withmissing data for diabetes, leaving 47 834 individuals foranalysis. Subjects completed a questionnaire on medicalhistory, past and current diseases, use of medication, andhealth behavior. The questionnaire also included infor-mation on previous pregnancies and childbirth. Womenwere asked how many times they had been pregnant andhow many children were born. In the present study, SAFwas calculated as the mean of three consecutivemeasurements using an AGE Reader (DiagnOpticsCorrespondenceBruce H.R. Wolffenbuttel, Department of Endocrinology, UniversityMedical Center Groningen, HPC AA31, P.O. Box 30001, 9700 RBGroningen, The Netherlands.Tel: +31 50 3613962Fax: +31 50 3619392Email: bwo@umcg.nlReceived 25 December 2017; revised 20 April 2018; accepted 15May 2018doi: 10.1111/1753-0407.12782Highlights• Skin autofluorescence (SAF) assesses subcutaneous accumulation of advanced glycation end products and hasbeen shown to predict future cardiovascular disease and diabetes.• A higher number of pregnancies was significantly associated with higher SAF, even after correction for relevantconfounders like waist circumference, creatinine clearance, and diabetes status, but not after correction for age.• Women with the highest SAF Z-score had a more unfavorable risk factor profile, with higher body mass indexand waist circumference, higher blood pressure, lower high-density lipoprotein cholesterol, and higher triglycer-ide levels.Journal of Diabetes 10 (2018), 899–901© 2018 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,provided the original work is properly cited.899Technologies, Groningen, Netherlands).3 Age-adjustedSAF (Z-scores) was calculated because SAF is stronglyaffected by aging.3Data are given as the mean SD or as the median withinterquartile range (IQR) in the case of non-normallydistributed data. Linear regression analysis was per-formed to examine the association between the numberof pregnancies and SAF. In the multivariate models, weadjusted for relevant factors, such as waist circumference,body mass index (BMI), renal function, and smoking.Two-tailed P < 0.001 was considered significant.ResultsThe clinical characteristics of the study population aregiven in Table S1, available as Supplementary Materialto this paper. Mean subject age was 44 12 years,mean waist circumference was 87 12 cm, and meanBMI was 25.8 4.6 kg/m2. The median number ofpregnancies was 2.0 (IQR 1.0–3.0). In total, 20.5% ofwomen had not been pregnant, 42% reported one totwo pregnancies, 30% reported three to four pregnan-cies, and 7.5% reported five or more pregnancies. Ahigher number of pregnancies was associated withhigher SAF, which persisted after correction for waistcircumference and renal function (P < 0.0001). How-ever, after further correction for age, SAF was no lon-ger associated with the number of pregnancies(P = 0.713; Table 1). Fig. 1 shows that SAF Z-scoresare comparable in the various groups of women dividedaccording to the number of pregnancies. Women in thehighest quartile of the SAF Z-score had a higher preva-lence of metabolic syndrome, as well as higher BMI,waist circumference, glucose, HbA1c, and lipids (allP < 0.01) than women in the other three quartiles, anda similar number of pregnancies compared with thosein the lowest quartile (Table S2).DiscussionAfter correction for important confounders, SAFincreased with the number of pregnancies in womenfrom the general population. However, after correctionfor age, this association was no longer significant. Theincreased oxidative stress that occurs during pregnancymay significantly affect SAF measurements. Indeed, ithas been reported that SAF is elevated in women withpre-eclampsia and associated with increased carotidartery intima–media thickness, a marker for atheroscle-rosis.4 Moreover, SAF was associated with higherblood pressure, triglycerides, and C-reactive proteinlevels, indicating the potential cardiovascular risk asso-ciated with these factors.5 Therefore, we postulate thatthe effect of pregnancy on SAF may only be restrictedto pathological pregnancies, such as those complicatedby pre-eclampsia.4,5 Unfortunately, the Lifelines datasetdid not record any complications of pregnancy.Two important studies have reported on the associa-tion between reproductive history and cardiovascularhealth. One of these studies reported that a higher num-ber of pregnancies was associated with lower cardiovascu-lar mortality,6 whereas the other study showed that theTable 1 Univariate and multivariate analyses for skinautofluorescenceModel Parameters β P-value R2 (%)1 No. pregnancies 0.061 <0.0001 5.32 No. pregnancies 0.0003 0.800 30.7Age 0.020 <0.00013 No. pregnancies 0.0031 <0.0001 19.7Waist 0.013 <0.0001GFR −0.006 <0.00014 No. pregnancies 0.030 <0.0001 20.5Waist 0.012 <0.0001GFR −0.006 <0.0001Diabetes or glucose 0.084 <0.00015 No. pregnancies −0.0001 0.941 31.3Age 0.17 <0.0001Waist 0.004 <0.0001GFR −0.001 <0.0001Diabetes 0.015 <0.0001GFR, glomerular filtration rate.4.03.02.01.00.0-1.0SAF (Z-score)-2.0-3.0-4.00 1–2 3–4No. pregnancies 5–6 ≥7Figure 1 Number of pregnancies and age-corrected skin autofluor-escence (SAF) Z-score. The boxes show the interquartile range, withthe median value indicated by the horizontal line; whiskers showthe range. Dots indicate outliers.900 © 2018 The Authors.Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.Research Letter R.P. VAN WAATERINGE et al.number of pregnancies or live births was associated withhigher left ventricular mass and end-systolic volume.7 Arecent review suggested that pre-eclampsia is an under-recognized risk factor for ischemic heart disease, chronichypertension, peripheral vascular disease, and stroke.8In conclusion, in the present study SAF increasedwith a higher number of pregnancies, but not aftercorrection for participants’ age. Those with the highestage-corrected SAF had a worse risk factor profile forfuture cardiovascular disease.AcknowledgementsThe authors acknowledge all the participants of the Life-lines Cohort Study and everybody involved in the set-upand implementation of the study. Lifelines has beenfunded by a number of public sources, notably the DutchGovernment, The Netherlands Organization of ScientificResearch NWO (Grant 175.010.2007.006), the NorthernNetherlands Collaboration of Provinces (SNN), theEuropean Fund for Regional Development, Dutch Minis-try of Economic Affairs, Pieken in de Delta, Provinces ofGroningen and Drenthe, the Target project, BBMRI-NL(Biobanking and BioMolecular resources Research Infra-structure The Netherlands), the University of Groningen,and the University Medical Center Groningen. This workwas supported by the National Consortium for HealthyAgeing, and funds from the European Union’s SeventhFramework Program (FP7/2007–2013) through the Bio-bank Standardisation and Harmonisation for ResearchExcellence in the European Union (BioSHaRE-EU) pro-ject (Grant agreement 261433). Lifelines (BRIF4568) isengaged in a Bioresource research impact factor (BRIF)policy pilot study, details of which can be found at:https://www.bioshare.eu/content/bioresource-impact-factor(accessed 24 December 2017).DisclosureNone declared.References1. Toescu V, Nuttall SL, Martin U, Kendall MJ, Dunne F.Oxidative stress and normal pregnancy. Clin Endocrinol(Oxf ). 2002; 57: 609–13.2. De Ranitz-Greven WL, Kaasenbrood L, Poucki WKet al. Advanced glycation end products, measured as skinautofluorescence, during normal pregnancy and preg-nancy complicated by diabetes mellitus. Diabetes TechnolTher. 2012; 14: 1134–9.3. Meerwaldt R, Graaff R, Oomen PHN et al. Simple non-invasive assessment of advanced glycation endproductaccumulation. Diabetologia. 2004; 47: 1324–30.4. Blaauw J, Smit AJ, van Pampus MG et al. Skin auto-fluorescence, a marker of advanced glycation end prod-ucts and oxidative stress, is increased in recentlypreeclamptic women. Am J Obstet Gynecol. 2006; 195:717–22.5. Coffeng SM, Blaauw J, Souwer ET et al. Skin autofluor-escence as marker of tissue advanced glycation end-products accumulation in formerly preeclamptic women.Hypertens Pregnancy. 2011; 30: 231–42.6. Jacobs MB, Kritz-Silverstein D, Wingard DL, Barrett-Connor E. The association of reproductive history withall-cause and cardiovascular mortality in older women:The Rancho Bernardo Study. Fertil Steril. 2012; 97:118–24.7. Parikh NI, Lloyd-Jones DM, Ning H et al. Association ofnumber of live births with left ventricular structure andfunction. The Multi-Ethnic Study of Atherosclerosis(MESA). Am Heart J. 2012; 163: 470–6.8. Ahmed R, Dunford J, Mehran R, Robson S,Kunadian V. Pre-eclampsia and future cardiovascular riskamong women a review. J Am Coll Cardiol. 2014; 63:1815–22.Supporting informationAdditional supporting information may be found online inthe Supporting Information section at the end of thearticle:Table S1. Baseline characteristics of the participatingwomen.Table S2. Skin autofluorescence Z-scores and cardiovascu-lar risk factors.© 2018 The Authors.Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.901R.P. VAN WAATERINGE et al. Research Letter

University of Groningen Research Database

  
 University of Groningen
Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is not
related to the number of pregnancies
van Waateringe, Robert; Truyens, Laura; van den Berg, Paul; Lutgers, Helen L.; Wolffenbutel,
B.H.
Published in:
Journal of diabetes
DOI:
10.1111/1753-0407.12782
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
2018
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Van Waateringe, R. P., Truyens, L., Van Den Berg, P. P., Lutgers, H. L., & Wolffenbuttel, B. H. R. (2018).
Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is not related to the
number of pregnancies. Journal of diabetes, 10(11), 899-901. DOI: 10.1111/1753-0407.12782
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the
author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately
and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the
number of authors shown on this cover page is limited to 10 maximum.
Download date: 28-11-2018
RESEARCH LETTER
Skin autoﬂuorescence, a non-invasive biomarker for
advanced glycation end products, is not related to the
number of pregnancies
Robert P. VAN WAATERINGE,1 Laura TRUYENS,2 Paul P. VAN DEN BERG,3 Helen L. LUTGERS4 and
Bruce H.R. WOLFFENBUTTEL 1
1Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, 2University of
Louvain, Louvain, Belgium, 3Department of Gynecology, University of Groningen, University Medical Center Groningen, Groningen, The
Netherlands, and 4Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands
Keywords: aging, diabetes, epidemiology, pregnancy, skin autoﬂuorescence.
To the Editor
The role of advanced glycation end products (AGEs)
in the pathophysiology of diabetes-related complica-
tions and aging has been studied extensively. The AGEs
represent chronic exposure to hyperglycemia and oxida-
tive stress. Tissue AGE accumulation can be assessed
non-invasively by measuring skin autoﬂuorescence
(SAF) with a so-called AGE reader. Markers of oxida-
tive stress are elevated during pregnancy, which can, in
turn, increase the formation of AGEs.1 One study
reported that SAF levels were higher in pregnant
women with pre-existing diabetes than in women with
gestational diabetes and women without diabetes.2
Preliminary data from our group suggested that SAF
increases during pregnancy and does not return to pre-
pregnancy levels (B. Groen et al., unpublished data,
2014). This phenomenon may be caused by increased
oxidative and glycemic stress during pregnancy. There-
fore, the aim of the present study was to assess the rela-
tionship between SAF and the number of pregnancies.
Methods
Subjects included in the study were participants from the
Lifelines Cohort Study, a large population-based cohort
study in the northern region of the Netherlands (www.
lifelines.net, accessed 24 December 2017). The Lifelines
study was approved by the Medical Ethics Committee of
the University Medical Center Groningen. Written
informed consent was obtained from all participants.
The present study included women of Western European
descent aged between 18 and 80 years for whom an SAF
measurement was available. Subjects with type 1 and
type 2 diabetes were excluded, as were as those with
missing data for diabetes, leaving 47 834 individuals for
analysis. Subjects completed a questionnaire on medical
history, past and current diseases, use of medication, and
health behavior. The questionnaire also included infor-
mation on previous pregnancies and childbirth. Women
were asked how many times they had been pregnant and
how many children were born. In the present study, SAF
was calculated as the mean of three consecutive
measurements using an AGE Reader (DiagnOptics
Correspondence
Bruce H.R. Wolffenbuttel, Department of Endocrinology, University
Medical Center Groningen, HPC AA31, P.O. Box 30001, 9700 RB
Groningen, The Netherlands.
Tel: +31 50 3613962
Fax: +31 50 3619392
Email: bwo@umcg.nl
Received 25 December 2017; revised 20 April 2018; accepted 15
May 2018
doi: 10.1111/1753-0407.12782
Highlights
• Skin autoﬂuorescence (SAF) assesses subcutaneous accumulation of advanced glycation end products and has
been shown to predict future cardiovascular disease and diabetes.
• A higher number of pregnancies was signiﬁcantly associated with higher SAF, even after correction for relevant
confounders like waist circumference, creatinine clearance, and diabetes status, but not after correction for age.
• Women with the highest SAF Z-score had a more unfavorable risk factor proﬁle, with higher body mass index
and waist circumference, higher blood pressure, lower high-density lipoprotein cholesterol, and higher triglycer-
ide levels.
Journal of Diabetes 10 (2018), 899–901
© 2018 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
899
Technologies, Groningen, Netherlands).3 Age-adjusted
SAF (Z-scores) was calculated because SAF is strongly
affected by aging.3
Data are given as the mean SD or as the median with
interquartile range (IQR) in the case of non-normally
distributed data. Linear regression analysis was per-
formed to examine the association between the number
of pregnancies and SAF. In the multivariate models, we
adjusted for relevant factors, such as waist circumference,
body mass index (BMI), renal function, and smoking.
Two-tailed P < 0.001 was considered signiﬁcant.
Results
The clinical characteristics of the study population are
given in Table S1, available as Supplementary Material
to this paper. Mean subject age was 44 12 years,
mean waist circumference was 87 12 cm, and mean
BMI was 25.8 4.6 kg/m2. The median number of
pregnancies was 2.0 (IQR 1.0–3.0). In total, 20.5% of
women had not been pregnant, 42% reported one to
two pregnancies, 30% reported three to four pregnan-
cies, and 7.5% reported ﬁve or more pregnancies. A
higher number of pregnancies was associated with
higher SAF, which persisted after correction for waist
circumference and renal function (P < 0.0001). How-
ever, after further correction for age, SAF was no lon-
ger associated with the number of pregnancies
(P = 0.713; Table 1). Fig. 1 shows that SAF Z-scores
are comparable in the various groups of women divided
according to the number of pregnancies. Women in the
highest quartile of the SAF Z-score had a higher preva-
lence of metabolic syndrome, as well as higher BMI,
waist circumference, glucose, HbA1c, and lipids (all
P < 0.01) than women in the other three quartiles, and
a similar number of pregnancies compared with those
in the lowest quartile (Table S2).
Discussion
After correction for important confounders, SAF
increased with the number of pregnancies in women
from the general population. However, after correction
for age, this association was no longer signiﬁcant. The
increased oxidative stress that occurs during pregnancy
may signiﬁcantly affect SAF measurements. Indeed, it
has been reported that SAF is elevated in women with
pre-eclampsia and associated with increased carotid
artery intima–media thickness, a marker for atheroscle-
rosis.4 Moreover, SAF was associated with higher
blood pressure, triglycerides, and C-reactive protein
levels, indicating the potential cardiovascular risk asso-
ciated with these factors.5 Therefore, we postulate that
the effect of pregnancy on SAF may only be restricted
to pathological pregnancies, such as those complicated
by pre-eclampsia.4,5 Unfortunately, the Lifelines dataset
did not record any complications of pregnancy.
Two important studies have reported on the associa-
tion between reproductive history and cardiovascular
health. One of these studies reported that a higher num-
ber of pregnancies was associated with lower cardiovascu-
lar mortality,6 whereas the other study showed that the
Table 1 Univariate and multivariate analyses for skin
autoﬂuorescence
Model Parameters β P-value R2 (%)
1 No. pregnancies 0.061 <0.0001 5.3
2 No. pregnancies 0.0003 0.800 30.7
Age 0.020 <0.0001
3 No. pregnancies 0.0031 <0.0001 19.7
Waist 0.013 <0.0001
GFR −0.006 <0.0001
4 No. pregnancies 0.030 <0.0001 20.5
Waist 0.012 <0.0001
GFR −0.006 <0.0001
Diabetes or glucose 0.084 <0.0001
5 No. pregnancies −0.0001 0.941 31.3
Age 0.17 <0.0001
Waist 0.004 <0.0001
GFR −0.001 <0.0001
Diabetes 0.015 <0.0001
GFR, glomerular ﬁltration rate.
4.0
3.0
2.0
1.0
0.0
-1.0S
A
F
 (
Z
-s
co
re
)
-2.0
-3.0
-4.0
0 1–2 3–4
No. pregnancies 
5–6 ≥7
Figure 1 Number of pregnancies and age-corrected skin autoﬂuor-
escence (SAF) Z-score. The boxes show the interquartile range, with
the median value indicated by the horizontal line; whiskers show
the range. Dots indicate outliers.
900 © 2018 The Authors.
Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.
Research Letter R.P. VAN WAATERINGE et al.
number of pregnancies or live births was associated with
higher left ventricular mass and end-systolic volume.7 A
recent review suggested that pre-eclampsia is an under-
recognized risk factor for ischemic heart disease, chronic
hypertension, peripheral vascular disease, and stroke.8
In conclusion, in the present study SAF increased
with a higher number of pregnancies, but not after
correction for participants’ age. Those with the highest
age-corrected SAF had a worse risk factor proﬁle for
future cardiovascular disease.
Acknowledgements
The authors acknowledge all the participants of the Life-
lines Cohort Study and everybody involved in the set-up
and implementation of the study. Lifelines has been
funded by a number of public sources, notably the Dutch
Government, The Netherlands Organization of Scientiﬁc
Research NWO (Grant 175.010.2007.006), the Northern
Netherlands Collaboration of Provinces (SNN), the
European Fund for Regional Development, Dutch Minis-
try of Economic Affairs, Pieken in de Delta, Provinces of
Groningen and Drenthe, the Target project, BBMRI-NL
(Biobanking and BioMolecular resources Research Infra-
structure The Netherlands), the University of Groningen,
and the University Medical Center Groningen. This work
was supported by the National Consortium for Healthy
Ageing, and funds from the European Union’s Seventh
Framework Program (FP7/2007–2013) through the Bio-
bank Standardisation and Harmonisation for Research
Excellence in the European Union (BioSHaRE-EU) pro-
ject (Grant agreement 261433). Lifelines (BRIF4568) is
engaged in a Bioresource research impact factor (BRIF)
policy pilot study, details of which can be found at:
https://www.bioshare.eu/content/bioresource-impact-factor
(accessed 24 December 2017).
Disclosure
None declared.
References
1. Toescu V, Nuttall SL, Martin U, Kendall MJ, Dunne F.
Oxidative stress and normal pregnancy. Clin Endocrinol
(Oxf ). 2002; 57: 609–13.
2. De Ranitz-Greven WL, Kaasenbrood L, Poucki WK
et al. Advanced glycation end products, measured as skin
autoﬂuorescence, during normal pregnancy and preg-
nancy complicated by diabetes mellitus. Diabetes Technol
Ther. 2012; 14: 1134–9.
3. Meerwaldt R, Graaff R, Oomen PHN et al. Simple non-
invasive assessment of advanced glycation endproduct
accumulation. Diabetologia. 2004; 47: 1324–30.
4. Blaauw J, Smit AJ, van Pampus MG et al. Skin auto-
ﬂuorescence, a marker of advanced glycation end prod-
ucts and oxidative stress, is increased in recently
preeclamptic women. Am J Obstet Gynecol. 2006; 195:
717–22.
5. Coffeng SM, Blaauw J, Souwer ET et al. Skin autoﬂuor-
escence as marker of tissue advanced glycation end-
products accumulation in formerly preeclamptic women.
Hypertens Pregnancy. 2011; 30: 231–42.
6. Jacobs MB, Kritz-Silverstein D, Wingard DL, Barrett-
Connor E. The association of reproductive history with
all-cause and cardiovascular mortality in older women:
The Rancho Bernardo Study. Fertil Steril. 2012; 97:
118–24.
7. Parikh NI, Lloyd-Jones DM, Ning H et al. Association of
number of live births with left ventricular structure and
function. The Multi-Ethnic Study of Atherosclerosis
(MESA). Am Heart J. 2012; 163: 470–6.
8. Ahmed R, Dunford J, Mehran R, Robson S,
Kunadian V. Pre-eclampsia and future cardiovascular risk
among women a review. J Am Coll Cardiol. 2014; 63:
1815–22.
Supporting information
Additional supporting information may be found online in
the Supporting Information section at the end of the
article:
Table S1. Baseline characteristics of the participating
women.
Table S2. Skin autoﬂuorescence Z-scores and cardiovascu-
lar risk factors.
© 2018 The Authors.
Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.
901
R.P. VAN WAATERINGE et al. Research Letter


NARCIS 

University of Groningen

University of GroningenSkin autofluorescence, a non-invasive biomarker for advanced glycation end products, is notrelated to the number of pregnanciesVan Waateringe, Robert P.; Truyens, Laura; Van Den Berg, Paul P.; Lutgers, Helen L.;Wolffenbuttel, Bruce H. R.Published in:Journal of diabetesDOI:10.1111/1753-0407.12782IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2018Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Van Waateringe, R. P., Truyens, L., Van Den Berg, P. P., Lutgers, H. L., & Wolffenbuttel, B. H. R. (2018).Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is not related to thenumber of pregnancies. Journal of diabetes, 10(11), 899-901. https://doi.org/10.1111/1753-0407.12782CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 31-12-2025RESEARCH LETTERSkin autofluorescence, a non-invasive biomarker foradvanced glycation end products, is not related to thenumber of pregnanciesRobert P. VAN WAATERINGE,1 Laura TRUYENS,2 Paul P. VAN DEN BERG,3 Helen L. LUTGERS4 andBruce H.R. WOLFFENBUTTEL 11Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, 2University ofLouvain, Louvain, Belgium, 3Department of Gynecology, University of Groningen, University Medical Center Groningen, Groningen, TheNetherlands, and 4Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, The NetherlandsKeywords: aging, diabetes, epidemiology, pregnancy, skin autofluorescence.To the EditorThe role of advanced glycation end products (AGEs)in the pathophysiology of diabetes-related complica-tions and aging has been studied extensively. The AGEsrepresent chronic exposure to hyperglycemia and oxida-tive stress. Tissue AGE accumulation can be assessednon-invasively by measuring skin autofluorescence(SAF) with a so-called AGE reader. Markers of oxida-tive stress are elevated during pregnancy, which can, inturn, increase the formation of AGEs.1 One studyreported that SAF levels were higher in pregnantwomen with pre-existing diabetes than in women withgestational diabetes and women without diabetes.2Preliminary data from our group suggested that SAFincreases during pregnancy and does not return to pre-pregnancy levels (B. Groen et al., unpublished data,2014). This phenomenon may be caused by increasedoxidative and glycemic stress during pregnancy. There-fore, the aim of the present study was to assess the rela-tionship between SAF and the number of pregnancies.MethodsSubjects included in the study were participants from theLifelines Cohort Study, a large population-based cohortstudy in the northern region of the Netherlands (www.lifelines.net, accessed 24 December 2017). The Lifelinesstudy was approved by the Medical Ethics Committee ofthe University Medical Center Groningen. Writteninformed consent was obtained from all participants.The present study included women of Western Europeandescent aged between 18 and 80 years for whom an SAFmeasurement was available. Subjects with type 1 andtype 2 diabetes were excluded, as were as those withmissing data for diabetes, leaving 47 834 individuals foranalysis. Subjects completed a questionnaire on medicalhistory, past and current diseases, use of medication, andhealth behavior. The questionnaire also included infor-mation on previous pregnancies and childbirth. Womenwere asked how many times they had been pregnant andhow many children were born. In the present study, SAFwas calculated as the mean of three consecutivemeasurements using an AGE Reader (DiagnOpticsCorrespondenceBruce H.R. Wolffenbuttel, Department of Endocrinology, UniversityMedical Center Groningen, HPC AA31, P.O. Box 30001, 9700 RBGroningen, The Netherlands.Tel: +31 50 3613962Fax: +31 50 3619392Email: bwo@umcg.nlReceived 25 December 2017; revised 20 April 2018; accepted 15May 2018doi: 10.1111/1753-0407.12782Highlights• Skin autofluorescence (SAF) assesses subcutaneous accumulation of advanced glycation end products and hasbeen shown to predict future cardiovascular disease and diabetes.• A higher number of pregnancies was significantly associated with higher SAF, even after correction for relevantconfounders like waist circumference, creatinine clearance, and diabetes status, but not after correction for age.• Women with the highest SAF Z-score had a more unfavorable risk factor profile, with higher body mass indexand waist circumference, higher blood pressure, lower high-density lipoprotein cholesterol, and higher triglycer-ide levels.Journal of Diabetes 10 (2018), 899–901© 2018 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,provided the original work is properly cited.899Technologies, Groningen, Netherlands).3 Age-adjustedSAF (Z-scores) was calculated because SAF is stronglyaffected by aging.3Data are given as the mean SD or as the median withinterquartile range (IQR) in the case of non-normallydistributed data. Linear regression analysis was per-formed to examine the association between the numberof pregnancies and SAF. In the multivariate models, weadjusted for relevant factors, such as waist circumference,body mass index (BMI), renal function, and smoking.Two-tailed P < 0.001 was considered significant.ResultsThe clinical characteristics of the study population aregiven in Table S1, available as Supplementary Materialto this paper. Mean subject age was 44 12 years,mean waist circumference was 87 12 cm, and meanBMI was 25.8 4.6 kg/m2. The median number ofpregnancies was 2.0 (IQR 1.0–3.0). In total, 20.5% ofwomen had not been pregnant, 42% reported one totwo pregnancies, 30% reported three to four pregnan-cies, and 7.5% reported five or more pregnancies. Ahigher number of pregnancies was associated withhigher SAF, which persisted after correction for waistcircumference and renal function (P < 0.0001). How-ever, after further correction for age, SAF was no lon-ger associated with the number of pregnancies(P = 0.713; Table 1). Fig. 1 shows that SAF Z-scoresare comparable in the various groups of women dividedaccording to the number of pregnancies. Women in thehighest quartile of the SAF Z-score had a higher preva-lence of metabolic syndrome, as well as higher BMI,waist circumference, glucose, HbA1c, and lipids (allP < 0.01) than women in the other three quartiles, anda similar number of pregnancies compared with thosein the lowest quartile (Table S2).DiscussionAfter correction for important confounders, SAFincreased with the number of pregnancies in womenfrom the general population. However, after correctionfor age, this association was no longer significant. Theincreased oxidative stress that occurs during pregnancymay significantly affect SAF measurements. Indeed, ithas been reported that SAF is elevated in women withpre-eclampsia and associated with increased carotidartery intima–media thickness, a marker for atheroscle-rosis.4 Moreover, SAF was associated with higherblood pressure, triglycerides, and C-reactive proteinlevels, indicating the potential cardiovascular risk asso-ciated with these factors.5 Therefore, we postulate thatthe effect of pregnancy on SAF may only be restrictedto pathological pregnancies, such as those complicatedby pre-eclampsia.4,5 Unfortunately, the Lifelines datasetdid not record any complications of pregnancy.Two important studies have reported on the associa-tion between reproductive history and cardiovascularhealth. One of these studies reported that a higher num-ber of pregnancies was associated with lower cardiovascu-lar mortality,6 whereas the other study showed that theTable 1 Univariate and multivariate analyses for skinautofluorescenceModel Parameters β P-value R2 (%)1 No. pregnancies 0.061 <0.0001 5.32 No. pregnancies 0.0003 0.800 30.7Age 0.020 <0.00013 No. pregnancies 0.0031 <0.0001 19.7Waist 0.013 <0.0001GFR −0.006 <0.00014 No. pregnancies 0.030 <0.0001 20.5Waist 0.012 <0.0001GFR −0.006 <0.0001Diabetes or glucose 0.084 <0.00015 No. pregnancies −0.0001 0.941 31.3Age 0.17 <0.0001Waist 0.004 <0.0001GFR −0.001 <0.0001Diabetes 0.015 <0.0001GFR, glomerular filtration rate.4.03.02.01.00.0-1.0SAF (Z-score)-2.0-3.0-4.00 1–2 3–4No. pregnancies 5–6 ≥7Figure 1 Number of pregnancies and age-corrected skin autofluor-escence (SAF) Z-score. The boxes show the interquartile range, withthe median value indicated by the horizontal line; whiskers showthe range. Dots indicate outliers.900 © 2018 The Authors.Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.Research Letter R.P. VAN WAATERINGE et al.number of pregnancies or live births was associated withhigher left ventricular mass and end-systolic volume.7 Arecent review suggested that pre-eclampsia is an under-recognized risk factor for ischemic heart disease, chronichypertension, peripheral vascular disease, and stroke.8In conclusion, in the present study SAF increasedwith a higher number of pregnancies, but not aftercorrection for participants’ age. Those with the highestage-corrected SAF had a worse risk factor profile forfuture cardiovascular disease.AcknowledgementsThe authors acknowledge all the participants of the Life-lines Cohort Study and everybody involved in the set-upand implementation of the study. Lifelines has beenfunded by a number of public sources, notably the DutchGovernment, The Netherlands Organization of ScientificResearch NWO (Grant 175.010.2007.006), the NorthernNetherlands Collaboration of Provinces (SNN), theEuropean Fund for Regional Development, Dutch Minis-try of Economic Affairs, Pieken in de Delta, Provinces ofGroningen and Drenthe, the Target project, BBMRI-NL(Biobanking and BioMolecular resources Research Infra-structure The Netherlands), the University of Groningen,and the University Medical Center Groningen. This workwas supported by the National Consortium for HealthyAgeing, and funds from the European Union’s SeventhFramework Program (FP7/2007–2013) through the Bio-bank Standardisation and Harmonisation for ResearchExcellence in the European Union (BioSHaRE-EU) pro-ject (Grant agreement 261433). Lifelines (BRIF4568) isengaged in a Bioresource research impact factor (BRIF)policy pilot study, details of which can be found at:https://www.bioshare.eu/content/bioresource-impact-factor(accessed 24 December 2017).DisclosureNone declared.References1. Toescu V, Nuttall SL, Martin U, Kendall MJ, Dunne F.Oxidative stress and normal pregnancy. Clin Endocrinol(Oxf ). 2002; 57: 609–13.2. De Ranitz-Greven WL, Kaasenbrood L, Poucki WKet al. Advanced glycation end products, measured as skinautofluorescence, during normal pregnancy and preg-nancy complicated by diabetes mellitus. Diabetes TechnolTher. 2012; 14: 1134–9.3. Meerwaldt R, Graaff R, Oomen PHN et al. Simple non-invasive assessment of advanced glycation endproductaccumulation. Diabetologia. 2004; 47: 1324–30.4. Blaauw J, Smit AJ, van Pampus MG et al. Skin auto-fluorescence, a marker of advanced glycation end prod-ucts and oxidative stress, is increased in recentlypreeclamptic women. Am J Obstet Gynecol. 2006; 195:717–22.5. Coffeng SM, Blaauw J, Souwer ET et al. Skin autofluor-escence as marker of tissue advanced glycation end-products accumulation in formerly preeclamptic women.Hypertens Pregnancy. 2011; 30: 231–42.6. Jacobs MB, Kritz-Silverstein D, Wingard DL, Barrett-Connor E. The association of reproductive history withall-cause and cardiovascular mortality in older women:The Rancho Bernardo Study. Fertil Steril. 2012; 97:118–24.7. Parikh NI, Lloyd-Jones DM, Ning H et al. Association ofnumber of live births with left ventricular structure andfunction. The Multi-Ethnic Study of Atherosclerosis(MESA). Am Heart J. 2012; 163: 470–6.8. Ahmed R, Dunford J, Mehran R, Robson S,Kunadian V. Pre-eclampsia and future cardiovascular riskamong women a review. J Am Coll Cardiol. 2014; 63:1815–22.Supporting informationAdditional supporting information may be found online inthe Supporting Information section at the end of thearticle:Table S1. Baseline characteristics of the participatingwomen.Table S2. Skin autofluorescence Z-scores and cardiovascu-lar risk factors.© 2018 The Authors.Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.901R.P. VAN WAATERINGE et al. Research Letter

   University of GroningenSkin autofluorescence, a non-invasive biomarker for advanced glycation end products, is notrelated to the number of pregnanciesVan Waateringe, Robert P.; Truyens, Laura; Van Den Berg, Paul P.; Lutgers, Helen L.;Wolffenbuttel, Bruce H. R.Published in:Journal of diabetesDOI:10.1111/1753-0407.12782IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2018Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Van Waateringe, R. P., Truyens, L., Van Den Berg, P. P., Lutgers, H. L., & Wolffenbuttel, B. H. R. (2018).Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is not related to thenumber of pregnancies. Journal of diabetes, 10(11), 899-901. https://doi.org/10.1111/1753-0407.12782CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 13-11-2019RESEARCH LETTERSkin autoﬂuorescence, a non-invasive biomarker foradvanced glycation end products, is not related to thenumber of pregnanciesRobert P. VAN WAATERINGE,1 Laura TRUYENS,2 Paul P. VAN DEN BERG,3 Helen L. LUTGERS4 andBruce H.R. WOLFFENBUTTEL 11Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, 2University ofLouvain, Louvain, Belgium, 3Department of Gynecology, University of Groningen, University Medical Center Groningen, Groningen, TheNetherlands, and 4Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, The NetherlandsKeywords: aging, diabetes, epidemiology, pregnancy, skin autoﬂuorescence.To the EditorThe role of advanced glycation end products (AGEs)in the pathophysiology of diabetes-related complica-tions and aging has been studied extensively. The AGEsrepresent chronic exposure to hyperglycemia and oxida-tive stress. Tissue AGE accumulation can be assessednon-invasively by measuring skin autoﬂuorescence(SAF) with a so-called AGE reader. Markers of oxida-tive stress are elevated during pregnancy, which can, inturn, increase the formation of AGEs.1 One studyreported that SAF levels were higher in pregnantwomen with pre-existing diabetes than in women withgestational diabetes and women without diabetes.2Preliminary data from our group suggested that SAFincreases during pregnancy and does not return to pre-pregnancy levels (B. Groen et al., unpublished data,2014). This phenomenon may be caused by increasedoxidative and glycemic stress during pregnancy. There-fore, the aim of the present study was to assess the rela-tionship between SAF and the number of pregnancies.MethodsSubjects included in the study were participants from theLifelines Cohort Study, a large population-based cohortstudy in the northern region of the Netherlands (www.lifelines.net, accessed 24 December 2017). The Lifelinesstudy was approved by the Medical Ethics Committee ofthe University Medical Center Groningen. Writteninformed consent was obtained from all participants.The present study included women of Western Europeandescent aged between 18 and 80 years for whom an SAFmeasurement was available. Subjects with type 1 andtype 2 diabetes were excluded, as were as those withmissing data for diabetes, leaving 47 834 individuals foranalysis. Subjects completed a questionnaire on medicalhistory, past and current diseases, use of medication, andhealth behavior. The questionnaire also included infor-mation on previous pregnancies and childbirth. Womenwere asked how many times they had been pregnant andhow many children were born. In the present study, SAFwas calculated as the mean of three consecutivemeasurements using an AGE Reader (DiagnOpticsCorrespondenceBruce H.R. Wolffenbuttel, Department of Endocrinology, UniversityMedical Center Groningen, HPC AA31, P.O. Box 30001, 9700 RBGroningen, The Netherlands.Tel: +31 50 3613962Fax: +31 50 3619392Email: bwo@umcg.nlReceived 25 December 2017; revised 20 April 2018; accepted 15May 2018doi: 10.1111/1753-0407.12782Highlights• Skin autoﬂuorescence (SAF) assesses subcutaneous accumulation of advanced glycation end products and hasbeen shown to predict future cardiovascular disease and diabetes.• A higher number of pregnancies was signiﬁcantly associated with higher SAF, even after correction for relevantconfounders like waist circumference, creatinine clearance, and diabetes status, but not after correction for age.• Women with the highest SAF Z-score had a more unfavorable risk factor proﬁle, with higher body mass indexand waist circumference, higher blood pressure, lower high-density lipoprotein cholesterol, and higher triglycer-ide levels.Journal of Diabetes 10 (2018), 899–901© 2018 The Authors. Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,provided the original work is properly cited.899Technologies, Groningen, Netherlands).3 Age-adjustedSAF (Z-scores) was calculated because SAF is stronglyaffected by aging.3Data are given as the mean SD or as the median withinterquartile range (IQR) in the case of non-normallydistributed data. Linear regression analysis was per-formed to examine the association between the numberof pregnancies and SAF. In the multivariate models, weadjusted for relevant factors, such as waist circumference,body mass index (BMI), renal function, and smoking.Two-tailed P < 0.001 was considered signiﬁcant.ResultsThe clinical characteristics of the study population aregiven in Table S1, available as Supplementary Materialto this paper. Mean subject age was 44 12 years,mean waist circumference was 87 12 cm, and meanBMI was 25.8 4.6 kg/m2. The median number ofpregnancies was 2.0 (IQR 1.0–3.0). In total, 20.5% ofwomen had not been pregnant, 42% reported one totwo pregnancies, 30% reported three to four pregnan-cies, and 7.5% reported ﬁve or more pregnancies. Ahigher number of pregnancies was associated withhigher SAF, which persisted after correction for waistcircumference and renal function (P < 0.0001). How-ever, after further correction for age, SAF was no lon-ger associated with the number of pregnancies(P = 0.713; Table 1). Fig. 1 shows that SAF Z-scoresare comparable in the various groups of women dividedaccording to the number of pregnancies. Women in thehighest quartile of the SAF Z-score had a higher preva-lence of metabolic syndrome, as well as higher BMI,waist circumference, glucose, HbA1c, and lipids (allP < 0.01) than women in the other three quartiles, anda similar number of pregnancies compared with thosein the lowest quartile (Table S2).DiscussionAfter correction for important confounders, SAFincreased with the number of pregnancies in womenfrom the general population. However, after correctionfor age, this association was no longer signiﬁcant. Theincreased oxidative stress that occurs during pregnancymay signiﬁcantly affect SAF measurements. Indeed, ithas been reported that SAF is elevated in women withpre-eclampsia and associated with increased carotidartery intima–media thickness, a marker for atheroscle-rosis.4 Moreover, SAF was associated with higherblood pressure, triglycerides, and C-reactive proteinlevels, indicating the potential cardiovascular risk asso-ciated with these factors.5 Therefore, we postulate thatthe effect of pregnancy on SAF may only be restrictedto pathological pregnancies, such as those complicatedby pre-eclampsia.4,5 Unfortunately, the Lifelines datasetdid not record any complications of pregnancy.Two important studies have reported on the associa-tion between reproductive history and cardiovascularhealth. One of these studies reported that a higher num-ber of pregnancies was associated with lower cardiovascu-lar mortality,6 whereas the other study showed that theTable 1 Univariate and multivariate analyses for skinautoﬂuorescenceModel Parameters β P-value R2 (%)1 No. pregnancies 0.061 <0.0001 5.32 No. pregnancies 0.0003 0.800 30.7Age 0.020 <0.00013 No. pregnancies 0.0031 <0.0001 19.7Waist 0.013 <0.0001GFR −0.006 <0.00014 No. pregnancies 0.030 <0.0001 20.5Waist 0.012 <0.0001GFR −0.006 <0.0001Diabetes or glucose 0.084 <0.00015 No. pregnancies −0.0001 0.941 31.3Age 0.17 <0.0001Waist 0.004 <0.0001GFR −0.001 <0.0001Diabetes 0.015 <0.0001GFR, glomerular ﬁltration rate.4.03.02.01.00.0-1.0SAF (Z-score)-2.0-3.0-4.00 1–2 3–4No. pregnancies 5–6 ≥7Figure 1 Number of pregnancies and age-corrected skin autoﬂuor-escence (SAF) Z-score. The boxes show the interquartile range, withthe median value indicated by the horizontal line; whiskers showthe range. Dots indicate outliers.900 © 2018 The Authors.Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.Research Letter R.P. VAN WAATERINGE et al.number of pregnancies or live births was associated withhigher left ventricular mass and end-systolic volume.7 Arecent review suggested that pre-eclampsia is an under-recognized risk factor for ischemic heart disease, chronichypertension, peripheral vascular disease, and stroke.8In conclusion, in the present study SAF increasedwith a higher number of pregnancies, but not aftercorrection for participants’ age. Those with the highestage-corrected SAF had a worse risk factor proﬁle forfuture cardiovascular disease.AcknowledgementsThe authors acknowledge all the participants of the Life-lines Cohort Study and everybody involved in the set-upand implementation of the study. Lifelines has beenfunded by a number of public sources, notably the DutchGovernment, The Netherlands Organization of ScientiﬁcResearch NWO (Grant 175.010.2007.006), the NorthernNetherlands Collaboration of Provinces (SNN), theEuropean Fund for Regional Development, Dutch Minis-try of Economic Affairs, Pieken in de Delta, Provinces ofGroningen and Drenthe, the Target project, BBMRI-NL(Biobanking and BioMolecular resources Research Infra-structure The Netherlands), the University of Groningen,and the University Medical Center Groningen. This workwas supported by the National Consortium for HealthyAgeing, and funds from the European Union’s SeventhFramework Program (FP7/2007–2013) through the Bio-bank Standardisation and Harmonisation for ResearchExcellence in the European Union (BioSHaRE-EU) pro-ject (Grant agreement 261433). Lifelines (BRIF4568) isengaged in a Bioresource research impact factor (BRIF)policy pilot study, details of which can be found at:https://www.bioshare.eu/content/bioresource-impact-factor(accessed 24 December 2017).DisclosureNone declared.References1. Toescu V, Nuttall SL, Martin U, Kendall MJ, Dunne F.Oxidative stress and normal pregnancy. Clin Endocrinol(Oxf ). 2002; 57: 609–13.2. De Ranitz-Greven WL, Kaasenbrood L, Poucki WKet al. Advanced glycation end products, measured as skinautoﬂuorescence, during normal pregnancy and preg-nancy complicated by diabetes mellitus. Diabetes TechnolTher. 2012; 14: 1134–9.3. Meerwaldt R, Graaff R, Oomen PHN et al. Simple non-invasive assessment of advanced glycation endproductaccumulation. Diabetologia. 2004; 47: 1324–30.4. Blaauw J, Smit AJ, van Pampus MG et al. Skin auto-ﬂuorescence, a marker of advanced glycation end prod-ucts and oxidative stress, is increased in recentlypreeclamptic women. Am J Obstet Gynecol. 2006; 195:717–22.5. Coffeng SM, Blaauw J, Souwer ET et al. Skin autoﬂuor-escence as marker of tissue advanced glycation end-products accumulation in formerly preeclamptic women.Hypertens Pregnancy. 2011; 30: 231–42.6. Jacobs MB, Kritz-Silverstein D, Wingard DL, Barrett-Connor E. The association of reproductive history withall-cause and cardiovascular mortality in older women:The Rancho Bernardo Study. Fertil Steril. 2012; 97:118–24.7. Parikh NI, Lloyd-Jones DM, Ning H et al. Association ofnumber of live births with left ventricular structure andfunction. The Multi-Ethnic Study of Atherosclerosis(MESA). Am Heart J. 2012; 163: 470–6.8. Ahmed R, Dunford J, Mehran R, Robson S,Kunadian V. Pre-eclampsia and future cardiovascular riskamong women a review. J Am Coll Cardiol. 2014; 63:1815–22.Supporting informationAdditional supporting information may be found online inthe Supporting Information section at the end of thearticle:Table S1. Baseline characteristics of the participatingwomen.Table S2. Skin autoﬂuorescence Z-scores and cardiovascu-lar risk factors.© 2018 The Authors.Journal of Diabetes published by John Wiley & Sons Australia, Ltd and Ruijin Hospital, Shanghai Jiaotong University School of Medicine.901R.P. VAN WAATERINGE et al. Research Letter

Skin autofluorescence, a non-invasive biomarker for advanced glycation end products, is not related to the number of pregnancies

Abstract

Similar works

Full text

Available Versions

ARTS repository - University of Groningen

Crossref

ARTS repository - University of Groningen

University of Groningen Research Database

NARCIS

ARTS repository - University of Groningen

University of Groningen

University of Groningen

University of Groningen