Advanced glycation endproducts (AGEs) are biomarkers of metabolic stress and are thought to contribute to the increase of long-term complications in chronic age-related diseases, such as diabetes and renal failure. Until recently, all AGE-assays needed invasive sampling. However, tissue autofluorescenceis related to the accumulation of AGEs. Therefore we developed a noninvasive Autofluorescence Reader (AFR), to measure skin GE accumulation noninvasively. The aims of this thesis were to validate the AFR as a measure of AGE accumulation, to evaluate skin autofluorescence as a clinical tool and its relationship with long-term complications in diabetes and renal failure. 

Zie: Summary

Meerwaldt, Robbert,

Meerwaldt, Robbert

ARTS repository - University of Groningen

   University of GroningenSkin autofluorescence and advanced glycation endproductsMeerwaldt, RobbertIMPORTANT 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:2005Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Meerwaldt, R. (2005). Skin autofluorescence and advanced glycation endproducts. s.n.CopyrightOther 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: 08-06-2022ummaryAdvanced glycation endproducts (AGEs) are biomarkers of metabolic stress and arerought to contribute to the increase of long-term complications in chronic age-relatediseases, such as diabetes and renal failure. Until recently, all AGE-assays needed invasiveampling. However, tissue autofluorescence is related to the accumulation of AGEs.lherefore we developed a noninvasive Autofluorescence Reader (AFR), to measure skin\GE accumulation noninvasively. The aims of this thesis were to validate the AFR as aneasure of AGE accumulation, to evaluate skin autofluorescence as a clinical tool and its:elationship with long-term complications in diabetes and renal failure.The AFR is indeed able to measure skin autofluorescence of the skin noninvasivelywith a high reproducibility. Measurements at different body sites (calf vs arm) showcomparable results and ,as discussed, the production and testing of different types of the AFR,including a version with a monochromator, have proceeded to application in various clinicalstudies (chapter 5). Skin autofluorescence measured with the AFR is related to theaccumulation of AGEs, i.e. collagen-linked fluorescence, pentosidine, andcarboxymethyllysine (CML). This relationship was found in healthy subjects, type I and lype2 diabetic patients, and hemodialysis patients (chapter 6,10).Increased levels of skin autofluorescence in diabetic patients are associated withparameters of metabolic burden (HbAlc, triglycerides, low density lipoproteins (LDL)) andwith renal dysfunction and ageing (chapter 6,8,9). In hemodialysis patients, skinautofluorescence is related to the presence of diabetes, hlperlipidaemia (triglycerides andLDL), duration of renal failure and dialysis treatment (chapter 10). Furthermore, a strongcorrelation between skin autofluorescence and inflammation (C-reactive protein) wasobserved in these patients. In "healthy" subjects, skin autofluorescence correlates with ageingand smoking habits (chapter 11). Overall, skin autofluorescence seems to be a biomarker ofageing, cumulative metabolic stress, and renal function.In diabetic patients, skin autofluorescence is strongly associated with the presence oflong{erm complications, including microvascular complications and coronary heart diseaseíCHD). Increased skin autofluorescence is associated with nerve conduction abnormalities(velocity and amplitude) and autonomic dysfunction (heart rate variability and baroreflexsensitivity), even before clinical manifestations ofdiabetic neuropathy (chapter 8). Increasedskin autofluorescence was also observed in patients with microalbuminuria, diabeticretinopathy, hypertension and CHD. Multivariate analysis showed that skin autofluorescencewas more strongly associated with long-term complications, compared to cument measures ofmetabolic burden, such as HbAlc or LDL. We hypothesizethat skin autofluorescence mayrepresent the long-term effects of a final comnon pathway for various risk factors. Thus,based on the present work, skin autofluorescence may integrate these factors and be moreinformative than the actual levels ofthese risk factors per se.Prospective mortality sfudies in this thesis showed that skin autofluorescence is astrong and independent predictor of mortality in diabetic patients and in hemodialysispatients. Again, skin autofluorescence r placed other measures of cumulative metabolic stressas predictors of survival. These results are the first to show the predictive value of AGEaccumulation (chapter 9,10).The original Maillard hypothesis on the formation of AGEs proposed that chemicalmodification of proteins by reducing sugars (glycation of proteins) in diabetes altered thestructure and function of tissue proteins, precipitating the development of diabeticcomplications. Interactions between AGEs and AGE specific receptors (e.g. RAGE) may be amajor mechanism by which AGEs contribute to the development of long-term complications.Interaction with RAGE results in the production of cytokines, which stimulates proliferationof mesangial cells, arterial smooth cells and increases collagen synthesis. Binding to RAGEfurther activates endothelial cells, resulting in higher levels ofendothelial adhesion moleculeslike VCAM-1, and activation of transcription factor NF-kB. Endothelial adhesion moleculesand NF-kB further increase monocyte adhesivity and vascular permeability, acceleratingatherosclerosis. AGEs initiate inflammatory-proliferative processes and propagateinflammation in established macrovascular disease. Trough the interaction with RAGE, AGEsinduce oxidative stress. AGEs modify LDL, making it less able to be cleared, promotinguptake by macrophages and inducing inflammation (chapter 2).Several limitations of the studies are discussed in this thesis. Not all AGEs exhibitfluorescent propeÍies. ELISA-based assays have shown increased accumulation of specificAGEs before increased autofluorescence in diabetes. Fluorescence represents group reactivity,which fails to provide quantitative information on concentrations of individual compounds.Importantly, the current understanding of physiological AGEs indicate that the major AGEsquantative are not fluorescent. Another limitation in our studies is that we do not yet know thedegree to which the relation of autofluorescence with AGE accumulation is affected by otherskin fluorophores such as the oxidation degradation product of tryptophan, N-formylkynurenine, or elastin linked fluorescence. In particular, advanced lipoxidationendproducts (ALE) may also contribute to tissue and skin autofluorescence.Skin autofluorescence is related to the accumulation of specifrc AGEs, cumulativemetabolic stress, and to long-term complications in diabetes and renal failure. Our studysupports the important clinical impact of AGE accumulation in the pathogenesis ofcardiovascular disease and warrants for interventions aimed at reducing AGE accumulation.The non-invasive AFR may become a clinical desktop tool for follow-up in metabolic controland risk assessment, but also provides a novel approach for monitoring the role of AGEs indisease. As expected, many questions have risen as our understanding of noninvasive skinautofluorescence measurements is increasing. Many are beyond the scope of this thesis. Atbest ow results on the presence of long-term complications are correlative, and it remains aquestion whether the correlation with survival is causative. Several follow-up studies havebeen started and are in progress. Will we discover the value of skin autofluorescence in dailyclinical practice?, or will it remain an Aladdin's magical lamp?

English

Skin autofluorescence and advanced glycation endproducts

University of Groningen Digital Archive

   University of GroningenSkin autofluorescence and advanced glycation endproductsMeerwaldt, RobbertIMPORTANT 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:2005Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Meerwaldt, R. (2005). Skin autofluorescence and advanced glycation endproducts. s.n.CopyrightOther 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: 09-09-2023ummaryAdvanced glycation endproducts (AGEs) are biomarkers of metabolic stress and arerought to contribute to the increase of long-term complications in chronic age-relatediseases, such as diabetes and renal failure. Until recently, all AGE-assays needed invasiveampling. However, tissue autofluorescence is related to the accumulation of AGEs.lherefore we developed a noninvasive Autofluorescence Reader (AFR), to measure skin\GE accumulation noninvasively. The aims of this thesis were to validate the AFR as aneasure of AGE accumulation, to evaluate skin autofluorescence as a clinical tool and its:elationship with long-term complications in diabetes and renal failure.The AFR is indeed able to measure skin autofluorescence of the skin noninvasivelywith a high reproducibility. Measurements at different body sites (calf vs arm) showcomparable results and ,as discussed, the production and testing of different types of the AFR,including a version with a monochromator, have proceeded to application in various clinicalstudies (chapter 5). Skin autofluorescence measured with the AFR is related to theaccumulation of AGEs, i.e. collagen-linked fluorescence, pentosidine, andcarboxymethyllysine (CML). This relationship was found in healthy subjects, type I and lype2 diabetic patients, and hemodialysis patients (chapter 6,10).Increased levels of skin autofluorescence in diabetic patients are associated withparameters of metabolic burden (HbAlc, triglycerides, low density lipoproteins (LDL)) andwith renal dysfunction and ageing (chapter 6,8,9). In hemodialysis patients, skinautofluorescence is related to the presence of diabetes, hlperlipidaemia (triglycerides andLDL), duration of renal failure and dialysis treatment (chapter 10). Furthermore, a strongcorrelation between skin autofluorescence and inflammation (C-reactive protein) wasobserved in these patients. In "healthy" subjects, skin autofluorescence correlates with ageingand smoking habits (chapter 11). Overall, skin autofluorescence seems to be a biomarker ofageing, cumulative metabolic stress, and renal function.In diabetic patients, skin autofluorescence is strongly associated with the presence oflong{erm complications, including microvascular complications and coronary heart diseaseíCHD). Increased skin autofluorescence is associated with nerve conduction abnormalities(velocity and amplitude) and autonomic dysfunction (heart rate variability and baroreflexsensitivity), even before clinical manifestations ofdiabetic neuropathy (chapter 8). Increasedskin autofluorescence was also observed in patients with microalbuminuria, diabeticretinopathy, hypertension and CHD. Multivariate analysis showed that skin autofluorescencewas more strongly associated with long-term complications, compared to cument measures ofmetabolic burden, such as HbAlc or LDL. We hypothesizethat skin autofluorescence mayrepresent the long-term effects of a final comnon pathway for various risk factors. Thus,based on the present work, skin autofluorescence may integrate these factors and be moreinformative than the actual levels ofthese risk factors per se.Prospective mortality sfudies in this thesis showed that skin autofluorescence is astrong and independent predictor of mortality in diabetic patients and in hemodialysispatients. Again, skin autofluorescence r placed other measures of cumulative metabolic stressas predictors of survival. These results are the first to show the predictive value of AGEaccumulation (chapter 9,10).The original Maillard hypothesis on the formation of AGEs proposed that chemicalmodification of proteins by reducing sugars (glycation of proteins) in diabetes altered thestructure and function of tissue proteins, precipitating the development of diabeticcomplications. Interactions between AGEs and AGE specific receptors (e.g. RAGE) may be amajor mechanism by which AGEs contribute to the development of long-term complications.Interaction with RAGE results in the production of cytokines, which stimulates proliferationof mesangial cells, arterial smooth cells and increases collagen synthesis. Binding to RAGEfurther activates endothelial cells, resulting in higher levels ofendothelial adhesion moleculeslike VCAM-1, and activation of transcription factor NF-kB. Endothelial adhesion moleculesand NF-kB further increase monocyte adhesivity and vascular permeability, acceleratingatherosclerosis. AGEs initiate inflammatory-proliferative processes and propagateinflammation in established macrovascular disease. Trough the interaction with RAGE, AGEsinduce oxidative stress. AGEs modify LDL, making it less able to be cleared, promotinguptake by macrophages and inducing inflammation (chapter 2).Several limitations of the studies are discussed in this thesis. Not all AGEs exhibitfluorescent propeÍies. ELISA-based assays have shown increased accumulation of specificAGEs before increased autofluorescence in diabetes. Fluorescence represents group reactivity,which fails to provide quantitative information on concentrations of individual compounds.Importantly, the current understanding of physiological AGEs indicate that the major AGEsquantative are not fluorescent. Another limitation in our studies is that we do not yet know thedegree to which the relation of autofluorescence with AGE accumulation is affected by otherskin fluorophores such as the oxidation degradation product of tryptophan, N-formylkynurenine, or elastin linked fluorescence. In particular, advanced lipoxidationendproducts (ALE) may also contribute to tissue and skin autofluorescence.Skin autofluorescence is related to the accumulation of specifrc AGEs, cumulativemetabolic stress, and to long-term complications in diabetes and renal failure. Our studysupports the important clinical impact of AGE accumulation in the pathogenesis ofcardiovascular disease and warrants for interventions aimed at reducing AGE accumulation.The non-invasive AFR may become a clinical desktop tool for follow-up in metabolic controland risk assessment, but also provides a novel approach for monitoring the role of AGEs indisease. As expected, many questions have risen as our understanding of noninvasive skinautofluorescence measurements is increasing. Many are beyond the scope of this thesis. Atbest ow results on the presence of long-term complications are correlative, and it remains aquestion whether the correlation with survival is causative. Several follow-up studies havebeen started and are in progress. Will we discover the value of skin autofluorescence in dailyclinical practice?, or will it remain an Aladdin's magical lamp?

University of Groningen

   University of GroningenSkin autofluorescence and advanced glycation endproductsMeerwaldt, RobbertIMPORTANT 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:2005Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Meerwaldt, R. (2005). Skin autofluorescence and advanced glycation endproducts. Groningen: s.n.CopyrightOther 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: 12-11-2019ummaryAdvanced glycation endproducts (AGEs) are biomarkers of metabolic stress and arerought to contribute to the increase of long-term complications in chronic age-relatediseases, such as diabetes and renal failure. Until recently, all AGE-assays needed invasiveampling. However, tissue autofluorescence is related to the accumulation of AGEs.lherefore we developed a noninvasive Autofluorescence Reader (AFR), to measure skin\GE accumulation noninvasively. The aims of this thesis were to validate the AFR as aneasure of AGE accumulation, to evaluate skin autofluorescence as a clinical tool and its:elationship with long-term complications in diabetes and renal failure.The AFR is indeed able to measure skin autofluorescence of the skin noninvasivelywith a high reproducibility. Measurements at different body sites (calf vs arm) showcomparable results and ,as discussed, the production and testing of different types of the AFR,including a version with a monochromator, have proceeded to application in various clinicalstudies (chapter 5). Skin autofluorescence measured with the AFR is related to theaccumulation of AGEs, i.e. collagen-linked fluorescence, pentosidine, andcarboxymethyllysine (CML). This relationship was found in healthy subjects, type I and lype2 diabetic patients, and hemodialysis patients (chapter 6,10).Increased levels of skin autofluorescence in diabetic patients are associated withparameters of metabolic burden (HbAlc, triglycerides, low density lipoproteins (LDL)) andwith renal dysfunction and ageing (chapter 6,8,9). In hemodialysis patients, skinautofluorescence is related to the presence of diabetes, hlperlipidaemia (triglycerides andLDL), duration of renal failure and dialysis treatment (chapter 10). Furthermore, a strongcorrelation between skin autofluorescence and inflammation (C-reactive protein) wasobserved in these patients. In "healthy" subjects, skin autofluorescence correlates with ageingand smoking habits (chapter 11). Overall, skin autofluorescence seems to be a biomarker ofageing, cumulative metabolic stress, and renal function.In diabetic patients, skin autofluorescence is strongly associated with the presence oflong{erm complications, including microvascular complications and coronary heart diseaseíCHD). Increased skin autofluorescence is associated with nerve conduction abnormalities(velocity and amplitude) and autonomic dysfunction (heart rate variability and baroreflexsensitivity), even before clinical manifestations ofdiabetic neuropathy (chapter 8). Increasedskin autofluorescence was also observed in patients with microalbuminuria, diabeticretinopathy, hypertension and CHD. Multivariate analysis showed that skin autofluorescencewas more strongly associated with long-term complications, compared to cument measures ofmetabolic burden, such as HbAlc or LDL. We hypothesizethat skin autofluorescence mayrepresent the long-term effects of a final comnon pathway for various risk factors. Thus,based on the present work, skin autofluorescence may integrate these factors and be moreinformative than the actual levels ofthese risk factors per se.Prospective mortality sfudies in this thesis showed that skin autofluorescence is astrong and independent predictor of mortality in diabetic patients and in hemodialysispatients. Again, skin autofluorescence r placed other measures of cumulative metabolic stressas predictors of survival. These results are the first to show the predictive value of AGEaccumulation (chapter 9,10).The original Maillard hypothesis on the formation of AGEs proposed that chemicalmodification of proteins by reducing sugars (glycation of proteins) in diabetes altered thestructure and function of tissue proteins, precipitating the development of diabeticcomplications. Interactions between AGEs and AGE specific receptors (e.g. RAGE) may be amajor mechanism by which AGEs contribute to the development of long-term complications.Interaction with RAGE results in the production of cytokines, which stimulates proliferationof mesangial cells, arterial smooth cells and increases collagen synthesis. Binding to RAGEfurther activates endothelial cells, resulting in higher levels ofendothelial adhesion moleculeslike VCAM-1, and activation of transcription factor NF-kB. Endothelial adhesion moleculesand NF-kB further increase monocyte adhesivity and vascular permeability, acceleratingatherosclerosis. AGEs initiate inflammatory-proliferative processes and propagateinflammation in established macrovascular disease. Trough the interaction with RAGE, AGEsinduce oxidative stress. AGEs modify LDL, making it less able to be cleared, promotinguptake by macrophages and inducing inflammation (chapter 2).Several limitations of the studies are discussed in this thesis. Not all AGEs exhibitfluorescent propeÍies. ELISA-based assays have shown increased accumulation of specificAGEs before increased autofluorescence in diabetes. Fluorescence represents group reactivity,which fails to provide quantitative information on concentrations of individual compounds.Importantly, the current understanding of physiological AGEs indicate that the major AGEsquantative are not fluorescent. Another limitation in our studies is that we do not yet know thedegree to which the relation of autofluorescence with AGE accumulation is affected by otherskin fluorophores such as the oxidation degradation product of tryptophan, N-formylkynurenine, or elastin linked fluorescence. In particular, advanced lipoxidationendproducts (ALE) may also contribute to tissue and skin autofluorescence.Skin autofluorescence is related to the accumulation of specifrc AGEs, cumulativemetabolic stress, and to long-term complications in diabetes and renal failure. Our studysupports the important clinical impact of AGE accumulation in the pathogenesis ofcardiovascular disease and warrants for interventions aimed at reducing AGE accumulation.The non-invasive AFR may become a clinical desktop tool for follow-up in metabolic controland risk assessment, but also provides a novel approach for monitoring the role of AGEs indisease. As expected, many questions have risen as our understanding of noninvasive skinautofluorescence measurements is increasing. Many are beyond the scope of this thesis. Atbest ow results on the presence of long-term complications are correlative, and it remains aquestion whether the correlation with survival is causative. Several follow-up studies havebeen started and are in progress. Will we discover the value of skin autofluorescence in dailyclinical practice?, or will it remain an Aladdin's magical lamp?

University of Groningen Research Database

  
 University of Groningen
Skin autofluorescence and advanced glycation endproducts
Meerwaldt, Robbert
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:
2005
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Meerwaldt, R. (2005). Skin autofluorescence and advanced glycation endproducts Groningen: s.n.
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: 11-02-2018
ummary
Advanced glycation endproducts (AGEs) are biomarkers of metabolic stress and are
rought to contribute to the increase of long-term complications in chronic age-related
iseases, such as diabetes and renal failure. Until recently, all AGE-assays needed invasive
ampling. However, tissue autofluorescence is related to the accumulation of AGEs.
lherefore we developed a noninvasive Autofluorescence Reader (AFR), to measure skin
\GE accumulation noninvasively. The aims of this thesis were to validate the AFR as a
neasure of AGE accumulation, to evaluate skin autofluorescence as a clinical tool and its
:elationship with long-term complications in diabetes and renal failure.
The AFR is indeed able to measure skin autofluorescence of the skin noninvasively
with a high reproducibility. Measurements at different body sites (calf vs arm) show
comparable results and ,as discussed, the production and testing of different types of the AFR,
including a version with a monochromator, have proceeded to application in various clinical
studies (chapter 5). Skin autofluorescence measured with the AFR is related to the
accumulation of AGEs, i.e. collagen-linked fluorescence, pentosidine, and
carboxymethyllysine (CML). This relationship was found in healthy subjects, type I and lype
2 diabetic patients, and hemodialysis patients (chapter 6,10).
Increased levels of skin autofluorescence in diabetic patients are associated with
parameters of metabolic burden (HbAlc, triglycerides, low density lipoproteins (LDL)) and
with renal dysfunction and ageing (chapter 6,8,9). In hemodialysis patients, skin
autofluorescence is related to the presence of diabetes, hlperlipidaemia (triglycerides and
LDL), duration of renal failure and dialysis treatment (chapter 10). Furthermore, a strong
correlation between skin autofluorescence and inflammation (C-reactive protein) was
observed in these patients. In "healthy" subjects, skin autofluorescence correlates with ageing
and smoking habits (chapter 11). Overall, skin autofluorescence seems to be a biomarker of
ageing, cumulative metabolic stress, and renal function.
In diabetic patients, skin autofluorescence is strongly associated with the presence of
long{erm complications, including microvascular complications and coronary heart disease
íCHD). Increased skin autofluorescence is associated with nerve conduction abnormalities
(velocity and amplitude) and autonomic dysfunction (heart rate variability and baroreflex
sensitivity), even before clinical manifestations ofdiabetic neuropathy (chapter 8). Increased
skin autofluorescence was also observed in patients with microalbuminuria, diabetic
retinopathy, hypertension and CHD. Multivariate analysis showed that skin autofluorescence
was more strongly associated with long-term complications, compared to cument measures of
metabolic burden, such as HbAlc or LDL. We hypothesizethat skin autofluorescence may
represent the long-term effects of a final comnon pathway for various risk factors. Thus,
based on the present work, skin autofluorescence may integrate these factors and be more
informative than the actual levels ofthese risk factors per se.
Prospective mortality sfudies in this thesis showed that skin autofluorescence is a
strong and independent predictor of mortality in diabetic patients and in hemodialysis
patients. Again, skin autofluorescence r placed other measures of cumulative metabolic stress
as predictors of survival. These results are the first to show the predictive value of AGE
accumulation (chapter 9,10).
The original Maillard hypothesis on the formation of AGEs proposed that chemical
modification of proteins by reducing sugars (glycation of proteins) in diabetes altered the
structure and function of tissue proteins, precipitating the development of diabetic
complications. Interactions between AGEs and AGE specific receptors (e.g. RAGE) may be a
major mechanism by which AGEs contribute to the development of long-term complications.
Interaction with RAGE results in the production of cytokines, which stimulates proliferation
of mesangial cells, arterial smooth cells and increases collagen synthesis. Binding to RAGE
further activates endothelial cells, resulting in higher levels ofendothelial adhesion molecules
like VCAM-1, and activation of transcription factor NF-kB. Endothelial adhesion molecules
and NF-kB further increase monocyte adhesivity and vascular permeability, accelerating
atherosclerosis. AGEs initiate inflammatory-proliferative processes and propagate
inflammation in established macrovascular disease. Trough the interaction with RAGE, AGEs
induce oxidative stress. AGEs modify LDL, making it less able to be cleared, promoting
uptake by macrophages and inducing inflammation (chapter 2).
Several limitations of the studies are discussed in this thesis. Not all AGEs exhibit
fluorescent propeÍies. ELISA-based assays have shown increased accumulation of specific
AGEs before increased autofluorescence in diabetes. Fluorescence represents group reactivity,
which fails to provide quantitative information on concentrations of individual compounds.
Importantly, the current understanding of physiological AGEs indicate that the major AGEs
quantative are not fluorescent. Another limitation in our studies is that we do not yet know the
degree to which the relation of autofluorescence with AGE accumulation is affected by other
skin fluorophores such as the oxidation degradation product of tryptophan, N-
formylkynurenine, or elastin linked fluorescence. In particular, advanced lipoxidation
endproducts (ALE) may also contribute to tissue and skin autofluorescence.
Skin autofluorescence is related to the accumulation of specifrc AGEs, cumulative
metabolic stress, and to long-term complications in diabetes and renal failure. Our study
supports the important clinical impact of AGE accumulation in the pathogenesis of
cardiovascular disease and warrants for interventions aimed at reducing AGE accumulation.
The non-invasive AFR may become a clinical desktop tool for follow-up in metabolic control
and risk assessment, but also provides a novel approach for monitoring the role of AGEs in
disease. As expected, many questions have risen as our understanding of noninvasive skin
autofluorescence measurements is increasing. Many are beyond the scope of this thesis. At
best ow results on the presence of long-term complications are correlative, and it remains a
question whether the correlation with survival is causative. Several follow-up studies have
been started and are in progress. Will we discover the value of skin autofluorescence in daily
clinical practice?, or will it remain an Aladdin's magical lamp?


Skin autofluorescence and advanced glycation endproducts

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