Urinary Collagen Fragments Are Significantly Altered in Diabetes: A Link to Pathophysiology
Identifieur interne : 002A41 ( Pmc/Curation ); précédent : 002A40; suivant : 002A42Urinary Collagen Fragments Are Significantly Altered in Diabetes: A Link to Pathophysiology
Auteurs : David M. Maahs [États-Unis] ; Justyna Siwy [Allemagne] ; Àngel Argilés [France] ; Marie Cerna [République tchèque] ; Christian Delles [Royaume-Uni] ; Anna F. Dominiczak [Royaume-Uni] ; Nathalie Gayrard [France] ; Alexander Iphöfer [Allemagne] ; Lothar J Nsch [Allemagne] ; George Jerums [Australie] ; Karel Medek [République tchèque] ; Harald Mischak [Allemagne, Royaume-Uni] ; Gerjan J. Navis [Pays-Bas] ; Johannes M. Roob [Autriche] ; Kasper Rossing [Danemark] ; Peter Rossing [Danemark] ; Ivan Rychlík [République tchèque] ; Eric Schiffer [Allemagne] ; Roland E. Schmieder [Allemagne] ; Thomas C. Wascher [Autriche] ; Brigitte M. Winklhofer-Roob [Autriche] ; Lukas U. Zimmerli [Royaume-Uni] ; Petra Zürbig [Allemagne] ; Janet K. Snell-Bergeon [États-Unis]Source :
- PLoS ONE [ 1932-6203 ] ; 2010.
Abstract
The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D).
Therefore, the low-molecular-weight urinary proteome of 902 subjects from 10 different centers, 315 controls and 587 patients with T1D (n = 299) or T2D (n = 288), was analyzed using capillary-electrophoresis mass-spectrometry. The 261 urinary biomarkers (100 were sequenced) previously discovered in 205 subjects were validated in an additional 697 subjects to distinguish DM subjects (n = 382) from control subjects (n = 315) with 94% (95% CI: 92–95) accuracy in this study. To identify biomarkers that differentiate T1D from T2D, a subset of normoalbuminuric patients with T1D (n = 68) and T2D (n = 42) was employed, enabling identification of 131 biomarker candidates (40 were sequenced) differentially regulated between T1D and T2D. These biomarkers distinguished T1D from T2D in an independent validation set of normoalbuminuric patients (n = 108) with 88% (95% CI: 81–94%) accuracy, and in patients with impaired renal function (n = 369) with 85% (95% CI: 81–88%) accuracy. Specific collagen fragments were associated with diabetes and type of diabetes indicating changes in collagen turnover and extracellular matrix as one hallmark of the molecular pathophysiology of diabetes. Additional biomarkers including inflammatory processes and pro-thrombotic alterations were observed.
These findings, based on the largest proteomic study performed to date on subjects with DM, validate the previously described biomarkers for DM, and pinpoint differences in the urinary proteome of T1D and T2D, indicating significant differences in extracellular matrix remodeling.
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DOI: 10.1371/journal.pone.0013051
PubMed: 20927192
PubMed Central: 2946909
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Schmieder</name><affiliation wicri:level="1"><nlm:aff id="aff12"><addr-line>Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen</wicri:regionArea></affiliation></author><author><name sortKey="Wascher, Thomas C" sort="Wascher, Thomas C" uniqKey="Wascher T" first="Thomas C." last="Wascher">Thomas C. Wascher</name><affiliation wicri:level="1"><nlm:aff id="aff13"><addr-line>Metabolism and Vascular Biology Research Group, Department of Internal Medicine, Medical University of Graz, Graz, Austria</addr-line></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Metabolism and Vascular Biology Research Group, Department of Internal Medicine, Medical University of Graz, Graz</wicri:regionArea></affiliation></author><author><name sortKey="Winklhofer Roob, Brigitte M" sort="Winklhofer Roob, Brigitte M" uniqKey="Winklhofer Roob B" first="Brigitte M." last="Winklhofer-Roob">Brigitte M. Winklhofer-Roob</name><affiliation wicri:level="1"><nlm:aff id="aff14"><addr-line>Human Nutrition and Metabolism Research Center (HNMRC), Institute of Molecular Biosciences, Karl-Franzens University of Graz, Graz, Austria</addr-line></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Human Nutrition and Metabolism Research Center (HNMRC), Institute of Molecular Biosciences, Karl-Franzens University of Graz, Graz</wicri:regionArea></affiliation></author><author><name sortKey="Zimmerli, Lukas U" sort="Zimmerli, Lukas U" uniqKey="Zimmerli L" first="Lukas U." last="Zimmerli">Lukas U. Zimmerli</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow</wicri:regionArea></affiliation></author><author><name sortKey="Zurbig, Petra" sort="Zurbig, Petra" uniqKey="Zurbig P" first="Petra" last="Zürbig">Petra Zürbig</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Mosaiques Diagnostics GmbH, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Mosaiques Diagnostics GmbH, Hannover</wicri:regionArea></affiliation></author><author><name sortKey="Snell Bergeon, Janet K" sort="Snell Bergeon, Janet K" uniqKey="Snell Bergeon J" first="Janet K." last="Snell-Bergeon">Janet K. Snell-Bergeon</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20927192</idno><idno type="pmc">2946909</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946909</idno><idno type="RBID">PMC:2946909</idno><idno type="doi">10.1371/journal.pone.0013051</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">002B91</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002B91</idno><idno type="wicri:Area/Pmc/Curation">002A41</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">002A41</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Urinary Collagen Fragments Are Significantly Altered in Diabetes: A Link to Pathophysiology</title><author><name sortKey="Maahs, David M" sort="Maahs, David M" uniqKey="Maahs D" first="David M." last="Maahs">David M. Maahs</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado</wicri:regionArea></affiliation></author><author><name sortKey="Siwy, Justyna" sort="Siwy, Justyna" uniqKey="Siwy J" first="Justyna" last="Siwy">Justyna Siwy</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Mosaiques Diagnostics GmbH, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Mosaiques Diagnostics GmbH, Hannover</wicri:regionArea></affiliation></author><author><name sortKey="Argiles, Angel" sort="Argiles, Angel" uniqKey="Argiles A" first="Àngel" last="Argilés">Àngel Argilés</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>RD – Néphrologie, Montpellier, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>RD – Néphrologie, Montpellier</wicri:regionArea></affiliation></author><author><name sortKey="Cerna, Marie" sort="Cerna, Marie" uniqKey="Cerna M" first="Marie" last="Cerna">Marie Cerna</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Department of General Biology and Genetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic</addr-line></nlm:aff><country xml:lang="fr">République tchèque</country><wicri:regionArea>Department of General Biology and Genetics, Third Faculty of Medicine, Charles University, Prague</wicri:regionArea></affiliation></author><author><name sortKey="Delles, Christian" sort="Delles, Christian" uniqKey="Delles C" first="Christian" last="Delles">Christian Delles</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow</wicri:regionArea></affiliation></author><author><name sortKey="Dominiczak, Anna F" sort="Dominiczak, Anna F" uniqKey="Dominiczak A" first="Anna F." last="Dominiczak">Anna F. Dominiczak</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow</wicri:regionArea></affiliation></author><author><name sortKey="Gayrard, Nathalie" sort="Gayrard, Nathalie" uniqKey="Gayrard N" first="Nathalie" last="Gayrard">Nathalie Gayrard</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>RD – Néphrologie, Montpellier, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>RD – Néphrologie, Montpellier</wicri:regionArea></affiliation></author><author><name sortKey="Iphofer, Alexander" sort="Iphofer, Alexander" uniqKey="Iphofer A" first="Alexander" last="Iphöfer">Alexander Iphöfer</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Department of Cell Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Cell Biology, Helmholtz Centre for Infection Research, Braunschweig</wicri:regionArea></affiliation></author><author><name sortKey="J Nsch, Lothar" sort="J Nsch, Lothar" uniqKey="J Nsch L" first="Lothar" last="J Nsch">Lothar J Nsch</name><affiliation wicri:level="1"><nlm:aff id="aff6"><addr-line>Department of Cell Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Cell Biology, Helmholtz Centre for Infection Research, Braunschweig</wicri:regionArea></affiliation></author><author><name sortKey="Jerums, George" sort="Jerums, George" uniqKey="Jerums G" first="George" last="Jerums">George Jerums</name><affiliation wicri:level="1"><nlm:aff id="aff7"><addr-line>Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia</addr-line></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea>Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria</wicri:regionArea></affiliation></author><author><name sortKey="Medek, Karel" sort="Medek, Karel" uniqKey="Medek K" first="Karel" last="Medek">Karel Medek</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Department of General Biology and Genetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic</addr-line></nlm:aff><country xml:lang="fr">République tchèque</country><wicri:regionArea>Department of General Biology and Genetics, Third Faculty of Medicine, Charles University, Prague</wicri:regionArea></affiliation></author><author><name sortKey="Mischak, Harald" sort="Mischak, Harald" uniqKey="Mischak H" first="Harald" last="Mischak">Harald Mischak</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Mosaiques Diagnostics GmbH, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Mosaiques Diagnostics GmbH, Hannover</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow</wicri:regionArea></affiliation></author><author><name sortKey="Navis, Gerjan J" sort="Navis, Gerjan J" uniqKey="Navis G" first="Gerjan J." last="Navis">Gerjan J. Navis</name><affiliation wicri:level="1"><nlm:aff id="aff8"><addr-line>Division of Nephrology, Department of Internal Medicine, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands</addr-line></nlm:aff><country xml:lang="fr">Pays-Bas</country><wicri:regionArea>Division of Nephrology, Department of Internal Medicine, University Medical Centre Groningen, University of Groningen, Groningen</wicri:regionArea></affiliation></author><author><name sortKey="Roob, Johannes M" sort="Roob, Johannes M" uniqKey="Roob J" first="Johannes M." last="Roob">Johannes M. Roob</name><affiliation wicri:level="1"><nlm:aff id="aff9"><addr-line>Division of Clinical Nephrology, Department of Internal Medicine, Medical University, Graz, Austria</addr-line></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Division of Clinical Nephrology, Department of Internal Medicine, Medical University, Graz</wicri:regionArea></affiliation></author><author><name sortKey="Rossing, Kasper" sort="Rossing, Kasper" uniqKey="Rossing K" first="Kasper" last="Rossing">Kasper Rossing</name><affiliation wicri:level="1"><nlm:aff id="aff10"><addr-line>Steno Diabetes Center, Gentofte, Denmark</addr-line></nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea>Steno Diabetes Center, Gentofte</wicri:regionArea></affiliation></author><author><name sortKey="Rossing, Peter" sort="Rossing, Peter" uniqKey="Rossing P" first="Peter" last="Rossing">Peter Rossing</name><affiliation wicri:level="1"><nlm:aff id="aff10"><addr-line>Steno Diabetes Center, Gentofte, Denmark</addr-line></nlm:aff><country xml:lang="fr">Danemark</country><wicri:regionArea>Steno Diabetes Center, Gentofte</wicri:regionArea></affiliation></author><author><name sortKey="Rychlik, Ivan" sort="Rychlik, Ivan" uniqKey="Rychlik I" first="Ivan" last="Rychlík">Ivan Rychlík</name><affiliation wicri:level="1"><nlm:aff id="aff11"><addr-line>Department of Internal Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic</addr-line></nlm:aff><country xml:lang="fr">République tchèque</country><wicri:regionArea>Department of Internal Medicine, Third Faculty of Medicine, Charles University, Prague</wicri:regionArea></affiliation></author><author><name sortKey="Schiffer, Eric" sort="Schiffer, Eric" uniqKey="Schiffer E" first="Eric" last="Schiffer">Eric Schiffer</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Mosaiques Diagnostics GmbH, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Mosaiques Diagnostics GmbH, Hannover</wicri:regionArea></affiliation></author><author><name sortKey="Schmieder, Roland E" sort="Schmieder, Roland E" uniqKey="Schmieder R" first="Roland E." last="Schmieder">Roland E. Schmieder</name><affiliation wicri:level="1"><nlm:aff id="aff12"><addr-line>Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen</wicri:regionArea></affiliation></author><author><name sortKey="Wascher, Thomas C" sort="Wascher, Thomas C" uniqKey="Wascher T" first="Thomas C." last="Wascher">Thomas C. Wascher</name><affiliation wicri:level="1"><nlm:aff id="aff13"><addr-line>Metabolism and Vascular Biology Research Group, Department of Internal Medicine, Medical University of Graz, Graz, Austria</addr-line></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Metabolism and Vascular Biology Research Group, Department of Internal Medicine, Medical University of Graz, Graz</wicri:regionArea></affiliation></author><author><name sortKey="Winklhofer Roob, Brigitte M" sort="Winklhofer Roob, Brigitte M" uniqKey="Winklhofer Roob B" first="Brigitte M." last="Winklhofer-Roob">Brigitte M. Winklhofer-Roob</name><affiliation wicri:level="1"><nlm:aff id="aff14"><addr-line>Human Nutrition and Metabolism Research Center (HNMRC), Institute of Molecular Biosciences, Karl-Franzens University of Graz, Graz, Austria</addr-line></nlm:aff><country xml:lang="fr">Autriche</country><wicri:regionArea>Human Nutrition and Metabolism Research Center (HNMRC), Institute of Molecular Biosciences, Karl-Franzens University of Graz, Graz</wicri:regionArea></affiliation></author><author><name sortKey="Zimmerli, Lukas U" sort="Zimmerli, Lukas U" uniqKey="Zimmerli L" first="Lukas U." last="Zimmerli">Lukas U. Zimmerli</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom</addr-line></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow</wicri:regionArea></affiliation></author><author><name sortKey="Zurbig, Petra" sort="Zurbig, Petra" uniqKey="Zurbig P" first="Petra" last="Zürbig">Petra Zürbig</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Mosaiques Diagnostics GmbH, Hannover, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Mosaiques Diagnostics GmbH, Hannover</wicri:regionArea></affiliation></author><author><name sortKey="Snell Bergeon, Janet K" sort="Snell Bergeon, Janet K" uniqKey="Snell Bergeon J" first="Janet K." last="Snell-Bergeon">Janet K. Snell-Bergeon</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D).</p></sec><sec><title>Methodology/Principal Findings</title><p>Therefore, the low-molecular-weight urinary proteome of 902 subjects from 10 different centers, 315 controls and 587 patients with T1D (n = 299) or T2D (n = 288), was analyzed using capillary-electrophoresis mass-spectrometry. The 261 urinary biomarkers (100 were sequenced) previously discovered in 205 subjects were validated in an additional 697 subjects to distinguish DM subjects (n = 382) from control subjects (n = 315) with 94% (95% CI: 92–95) accuracy in this study. To identify biomarkers that differentiate T1D from T2D, a subset of normoalbuminuric patients with T1D (n = 68) and T2D (n = 42) was employed, enabling identification of 131 biomarker candidates (40 were sequenced) differentially regulated between T1D and T2D. These biomarkers distinguished T1D from T2D in an independent validation set of normoalbuminuric patients (n = 108) with 88% (95% CI: 81–94%) accuracy, and in patients with impaired renal function (n = 369) with 85% (95% CI: 81–88%) accuracy. Specific collagen fragments were associated with diabetes and type of diabetes indicating changes in collagen turnover and extracellular matrix as one hallmark of the molecular pathophysiology of diabetes. Additional biomarkers including inflammatory processes and pro-thrombotic alterations were observed.</p></sec><sec><title>Conclusions/Significance</title><p>These findings, based on the largest proteomic study performed to date on subjects with DM, validate the previously described biomarkers for DM, and pinpoint differences in the urinary proteome of T1D and T2D, indicating significant differences in extracellular matrix remodeling.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Thongboonkerd, V" uniqKey="Thongboonkerd V">V Thongboonkerd</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kolch, W" uniqKey="Kolch W">W Kolch</name></author><author><name sortKey="Neususs, C" uniqKey="Neususs C">C Neususs</name></author><author><name sortKey="Pelzing, M" uniqKey="Pelzing M">M Pelzing</name></author><author><name sortKey="Mischak, H" uniqKey="Mischak H">H 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">20927192</article-id><article-id pub-id-type="pmc">2946909</article-id><article-id pub-id-type="publisher-id">10-PONE-RA-19553R1</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0013051</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline"><subject>Diabetes and Endocrinology</subject><subject>Diabetes and Endocrinology/Type 1 Diabetes</subject><subject>Diabetes and Endocrinology/Type 2 Diabetes</subject></subj-group></article-categories><title-group><article-title>Urinary Collagen Fragments Are Significantly Altered in Diabetes: A Link to Pathophysiology</article-title><alt-title alt-title-type="running-head">Urine Proteome & Diabetes Type</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Maahs</surname><given-names>David M.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Siwy</surname><given-names>Justyna</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Argilés</surname><given-names>Àngel</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cerna</surname><given-names>Marie</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Delles</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dominiczak</surname><given-names>Anna F.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gayrard</surname><given-names>Nathalie</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Iphöfer</surname><given-names>Alexander</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jänsch</surname><given-names>Lothar</given-names></name><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jerums</surname><given-names>George</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref></contrib><contrib contrib-type="author"><name><surname>Medek</surname><given-names>Karel</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mischak</surname><given-names>Harald</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Navis</surname><given-names>Gerjan J.</given-names></name><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Roob</surname><given-names>Johannes M.</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rossing</surname><given-names>Kasper</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rossing</surname><given-names>Peter</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rychlík</surname><given-names>Ivan</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schiffer</surname><given-names>Eric</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Schmieder</surname><given-names>Roland E.</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wascher</surname><given-names>Thomas C.</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Winklhofer-Roob</surname><given-names>Brigitte M.</given-names></name><xref ref-type="aff" rid="aff14"><sup>14</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zimmerli</surname><given-names>Lukas U.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zürbig</surname><given-names>Petra</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Snell-Bergeon</surname><given-names>Janet K.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Mosaiques Diagnostics GmbH, Hannover, Germany</addr-line></aff><aff id="aff3"><label>3</label><addr-line>RD – Néphrologie, Montpellier, France</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Department of General Biology and Genetics, Third Faculty of Medicine, Charles University, Prague, Czech Republic</addr-line></aff><aff id="aff5"><label>5</label><addr-line>BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Department of Cell Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia</addr-line></aff><aff id="aff8"><label>8</label><addr-line>Division of Nephrology, Department of Internal Medicine, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands</addr-line></aff><aff id="aff9"><label>9</label><addr-line>Division of Clinical Nephrology, Department of Internal Medicine, Medical University, Graz, Austria</addr-line></aff><aff id="aff10"><label>10</label><addr-line>Steno Diabetes Center, Gentofte, Denmark</addr-line></aff><aff id="aff11"><label>11</label><addr-line>Department of Internal Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic</addr-line></aff><aff id="aff12"><label>12</label><addr-line>Department of Nephrology and Hypertension, University of Erlangen-Nürnberg, Erlangen, Germany</addr-line></aff><aff id="aff13"><label>13</label><addr-line>Metabolism and Vascular Biology Research Group, Department of Internal Medicine, Medical University of Graz, Graz, Austria</addr-line></aff><aff id="aff14"><label>14</label><addr-line>Human Nutrition and Metabolism Research Center (HNMRC), Institute of Molecular Biosciences, Karl-Franzens University of Graz, Graz, Austria</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Fadini</surname><given-names>Gian Paolo</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">University of Padova, Medical School, Italy</aff><author-notes><corresp id="cor1">* E-mail: <email>David.Maahs@ucdenver.edu</email></corresp><fn fn-type="con"><p>Conceived and designed the experiments: DMM JS ÀA MC CD AFD NG AI LJ GJ KM HM GN JMR KR PR IR ES RES TCW BMWR LUZ PZ JKSB. Performed the experiments: JS HM ES PZ. Analyzed the data: JS ES PZ. Contributed reagents/materials/analysis tools: HM. Wrote the paper: DMM JS ÀA MC CD AFD NG AI LJ GJ KM HM GN JMR KR PR IR ES RES TCW BMWR LUZ PZ JKSB.</p></fn></author-notes><pub-date pub-type="collection"><year>2010</year></pub-date><pub-date pub-type="epub"><day>28</day><month>9</month><year>2010</year></pub-date><volume>5</volume><issue>9</issue><elocation-id>e13051</elocation-id><history><date date-type="received"><day>4</day><month>6</month><year>2010</year></date><date date-type="accepted"><day>23</day><month>8</month><year>2010</year></date></history><permissions><copyright-statement>Maahs et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</copyright-statement></permissions><abstract><sec><title>Background</title><p>The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D).</p></sec><sec><title>Methodology/Principal Findings</title><p>Therefore, the low-molecular-weight urinary proteome of 902 subjects from 10 different centers, 315 controls and 587 patients with T1D (n = 299) or T2D (n = 288), was analyzed using capillary-electrophoresis mass-spectrometry. The 261 urinary biomarkers (100 were sequenced) previously discovered in 205 subjects were validated in an additional 697 subjects to distinguish DM subjects (n = 382) from control subjects (n = 315) with 94% (95% CI: 92–95) accuracy in this study. To identify biomarkers that differentiate T1D from T2D, a subset of normoalbuminuric patients with T1D (n = 68) and T2D (n = 42) was employed, enabling identification of 131 biomarker candidates (40 were sequenced) differentially regulated between T1D and T2D. These biomarkers distinguished T1D from T2D in an independent validation set of normoalbuminuric patients (n = 108) with 88% (95% CI: 81–94%) accuracy, and in patients with impaired renal function (n = 369) with 85% (95% CI: 81–88%) accuracy. Specific collagen fragments were associated with diabetes and type of diabetes indicating changes in collagen turnover and extracellular matrix as one hallmark of the molecular pathophysiology of diabetes. Additional biomarkers including inflammatory processes and pro-thrombotic alterations were observed.</p></sec><sec><title>Conclusions/Significance</title><p>These findings, based on the largest proteomic study performed to date on subjects with DM, validate the previously described biomarkers for DM, and pinpoint differences in the urinary proteome of T1D and T2D, indicating significant differences in extracellular matrix remodeling.</p></sec></abstract><counts><page-count count="12"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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