C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction
C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction Andreas Schlotterer 1 , Georgi Kukudov 1 , Farastuk Bozorgmehr 1 , Harald Hutter 2 , Xueliang Du 3 , Dimitrios Oikonomou 1 , Youssef Ibrahim 1 , Friederike Pfisterer 1 , Naila Rabbani 4 , Paul Thornalley 4 , Ahmed Sayed...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2009-11, Vol.58 (11), p.2450-2456 |
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| creator | SCHLOTTERER, Andreas KUKUDOV, Georgi SAYED, Ahmed FLEMING, Thomas HUMPERT, Per SCHWENGER, Vedat ZEIER, Martin HAMANN, Andreas STERN, David BROWNLEE, Michael BIERHAUS, Angelika NAWROTH, Peter BOZORGMEHR, Farastuk MORCOS, Michael HUTTER, Harald XUELIANG DU OIKONOMOU, Dimitrios IBRAHIM, Youssef PFISTERER, Friederike RABBANI, Naila THORNALLEY, Paul |
| description | C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction
Andreas Schlotterer 1 ,
Georgi Kukudov 1 ,
Farastuk Bozorgmehr 1 ,
Harald Hutter 2 ,
Xueliang Du 3 ,
Dimitrios Oikonomou 1 ,
Youssef Ibrahim 1 ,
Friederike Pfisterer 1 ,
Naila Rabbani 4 ,
Paul Thornalley 4 ,
Ahmed Sayed 1 ,
Thomas Fleming 1 ,
Per Humpert 1 ,
Vedat Schwenger 1 ,
Martin Zeier 1 ,
Andreas Hamann 1 , 5 ,
David Stern 6 ,
Michael Brownlee 3 ,
Angelika Bierhaus 1 ,
Peter Nawroth 1 and
Michael Morcos 1
1 Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany;
2 Simon Fraser University, Department of Biological Sciences, Burnaby, Canada;
3 Departments of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York;
4 Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry, U.K.;
5 Diabetes-Clinic, Center for Vascular Medicine, Bad Nauheim, Germany;
6 College of Medicine, University of Cincinnati, Cincinnati, Ohio.
Corresponding author: Andreas Schlotterer, andreas.schlotterer{at}med.uni-heidelberg.de .
A.S., G.K., and F.B. contributed equally to this study.
Abstract
OBJECTIVE Establishing Caenorhabditis elegans as a model for glucose toxicity–mediated life span reduction.
RESEARCH DESIGN AND METHODS C. elegans were maintained to achieve glucose concentrations resembling the hyperglycemic conditions in diabetic patients. The effects
of high glucose on life span, glyoxalase-1 activity, advanced glycation end products (AGEs), and reactive oxygen species (ROS)
formation and on mitochondrial function were studied.
RESULTS High glucose conditions reduced mean life span from 18.5 ± 0.4 to 16.5 ± 0.6 days and maximum life span from 25.9 ± 0.4 to
23.2 ± 0.4 days, independent of glucose effects on cuticle or bacterial metabolization of glucose. The formation of methylglyoxal-modified
mitochondrial proteins and ROS was significantly increased by high glucose conditions and reduced by mitochondrial uncoupling
and complex IIIQo inhibition. Overexpression of the methylglyoxal–detoxifying enzyme glyoxalase-1 attenuated the life-shortening
effect of glucose by reducing AGE accumulation (by 65%) and ROS formation (by 50%) and restored mean (16.5 ± 0.6 to 20.6 ±
0.4 days) and maximum life span (23.2 ± 0.4 to 27.7 ± 2.3 days). In contrast, inhibition of glyoxalase-1 by RNAi further reduced
mean (16.5 ± 0.6 to 13.9 ± 0.7 days) and maximum life span (23.2 ± 0.4 to 20.3 ± 1.1 da |
| doi_str_mv | 10.2337/db09-0567 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_gale_infotracgeneralonefile_A211631757</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A211631757</galeid><sourcerecordid>A211631757</sourcerecordid><originalsourceid>FETCH-LOGICAL-c711t-213a89f068fafdbad256a89cdfd5dd5e4d45f74a981506e73ff74811740d206c3</originalsourceid><addsrcrecordid>eNp9kt-KEzEUxoMobrd64QtIULwQnJpkJsnMjbAU7QpdFv-BdyFNTqZZppPuZMZ173wH39AnMaXDroUiuUhy8jtfDud8CD2jZMbyXL61K1JlhAv5AE1olVdZzuT3h2hCCGUZlZU8QacxXhFCRFqP0QmthOQ0rybo03yGoYFatxHriC-ChQa70OF-DfhLP9hbHBw-9_UaL5rBhAh_fv3GF2C97sHipXcJ2-oWfwY7mN6H9gl65HQT4em4T9G3D--_zs-z5eXi4_xsmRlJaZ8xmuuyckSUTju70pZxkQLGOsut5VDYgjtZ6KqknAiQuUu3klJZEMuIMPkUvdvrbofVBqyBtu90o7ad3-juVgXt1eFL69eqDj8Uk6JMTUkCL0aBLlwPEHt1FYauTTUrRkVRVjzVOEUv91CtG1C-dSFpmY2PRp0xSkVOJZeJyo5QNbSQPg4tOJ_CB_zsCJ-WhY03RxNeHyQkpoeffa2HGFW5WP6vmJE1oUlzBpWGML88qm26EGMH7q6HlKidv9TOX2rnr8Q-_7fp9-RoqAS8GgEdjW5cp1vj4x3HGCkFZyxxb_bcOlnrxnegkqNW0EO8P_BSUapYwUn-Fy4L4vk</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>216489521</pqid></control><display><type>article</type><title>C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>SCHLOTTERER, Andreas ; KUKUDOV, Georgi ; SAYED, Ahmed ; FLEMING, Thomas ; HUMPERT, Per ; SCHWENGER, Vedat ; ZEIER, Martin ; HAMANN, Andreas ; STERN, David ; BROWNLEE, Michael ; BIERHAUS, Angelika ; NAWROTH, Peter ; BOZORGMEHR, Farastuk ; MORCOS, Michael ; HUTTER, Harald ; XUELIANG DU ; OIKONOMOU, Dimitrios ; IBRAHIM, Youssef ; PFISTERER, Friederike ; RABBANI, Naila ; THORNALLEY, Paul</creator><creatorcontrib>SCHLOTTERER, Andreas ; KUKUDOV, Georgi ; SAYED, Ahmed ; FLEMING, Thomas ; HUMPERT, Per ; SCHWENGER, Vedat ; ZEIER, Martin ; HAMANN, Andreas ; STERN, David ; BROWNLEE, Michael ; BIERHAUS, Angelika ; NAWROTH, Peter ; BOZORGMEHR, Farastuk ; MORCOS, Michael ; HUTTER, Harald ; XUELIANG DU ; OIKONOMOU, Dimitrios ; IBRAHIM, Youssef ; PFISTERER, Friederike ; RABBANI, Naila ; THORNALLEY, Paul</creatorcontrib><description>C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction
Andreas Schlotterer 1 ,
Georgi Kukudov 1 ,
Farastuk Bozorgmehr 1 ,
Harald Hutter 2 ,
Xueliang Du 3 ,
Dimitrios Oikonomou 1 ,
Youssef Ibrahim 1 ,
Friederike Pfisterer 1 ,
Naila Rabbani 4 ,
Paul Thornalley 4 ,
Ahmed Sayed 1 ,
Thomas Fleming 1 ,
Per Humpert 1 ,
Vedat Schwenger 1 ,
Martin Zeier 1 ,
Andreas Hamann 1 , 5 ,
David Stern 6 ,
Michael Brownlee 3 ,
Angelika Bierhaus 1 ,
Peter Nawroth 1 and
Michael Morcos 1
1 Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany;
2 Simon Fraser University, Department of Biological Sciences, Burnaby, Canada;
3 Departments of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York;
4 Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry, U.K.;
5 Diabetes-Clinic, Center for Vascular Medicine, Bad Nauheim, Germany;
6 College of Medicine, University of Cincinnati, Cincinnati, Ohio.
Corresponding author: Andreas Schlotterer, andreas.schlotterer{at}med.uni-heidelberg.de .
A.S., G.K., and F.B. contributed equally to this study.
Abstract
OBJECTIVE Establishing Caenorhabditis elegans as a model for glucose toxicity–mediated life span reduction.
RESEARCH DESIGN AND METHODS C. elegans were maintained to achieve glucose concentrations resembling the hyperglycemic conditions in diabetic patients. The effects
of high glucose on life span, glyoxalase-1 activity, advanced glycation end products (AGEs), and reactive oxygen species (ROS)
formation and on mitochondrial function were studied.
RESULTS High glucose conditions reduced mean life span from 18.5 ± 0.4 to 16.5 ± 0.6 days and maximum life span from 25.9 ± 0.4 to
23.2 ± 0.4 days, independent of glucose effects on cuticle or bacterial metabolization of glucose. The formation of methylglyoxal-modified
mitochondrial proteins and ROS was significantly increased by high glucose conditions and reduced by mitochondrial uncoupling
and complex IIIQo inhibition. Overexpression of the methylglyoxal–detoxifying enzyme glyoxalase-1 attenuated the life-shortening
effect of glucose by reducing AGE accumulation (by 65%) and ROS formation (by 50%) and restored mean (16.5 ± 0.6 to 20.6 ±
0.4 days) and maximum life span (23.2 ± 0.4 to 27.7 ± 2.3 days). In contrast, inhibition of glyoxalase-1 by RNAi further reduced
mean (16.5 ± 0.6 to 13.9 ± 0.7 days) and maximum life span (23.2 ± 0.4 to 20.3 ± 1.1 days). The life span reduction by glyoxalase-1
inhibition was independent from the insulin signaling pathway because high glucose conditions also affected daf-2 knockdown
animals in a similar manner.
CONCLUSIONS C. elegans is a suitable model organism to study glucose toxicity, in which high glucose conditions limit the life span by increasing
ROS formation and AGE modification of mitochondrial proteins in a daf-2 independent manner. Most importantly, glucose toxicity
can be prevented by improving glyoxalase-1–dependent methylglyoxal detoxification or preventing mitochondrial dysfunction.
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received April 22, 2009.
Accepted July 22, 2009.
© 2009 American Diabetes Association</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db09-0567</identifier><identifier>PMID: 19675139</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Age ; Animals ; Biological and medical sciences ; Caenorhabditis elegans ; Caenorhabditis elegans - growth & development ; Caenorhabditis elegans - metabolism ; Caenorhabditis elegans - ultrastructure ; Dextrose ; Diabetes ; Diabetes. Impaired glucose tolerance ; Diabetics ; Disease Models, Animal ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Enzymes ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Glucose ; Glucose - toxicity ; Health aspects ; Humans ; Hyperglycemia - metabolism ; Life Expectancy - trends ; Life span (Biology) ; Life spans (Biology) ; Longevity - physiology ; Medical sciences ; Metabolism ; Microscopy, Electron, Scanning ; Mitochondria - metabolism ; Nematodes ; Original ; Physiological aspects ; Proteins ; Reactive Oxygen Species - metabolism ; Research design ; Toxicity</subject><ispartof>Diabetes (New York, N.Y.), 2009-11, Vol.58 (11), p.2450-2456</ispartof><rights>2009 INIST-CNRS</rights><rights>COPYRIGHT 2009 American Diabetes Association</rights><rights>Copyright American Diabetes Association Nov 2009</rights><rights>2009 American Diabetes Association</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c711t-213a89f068fafdbad256a89cdfd5dd5e4d45f74a981506e73ff74811740d206c3</citedby><cites>FETCH-LOGICAL-c711t-213a89f068fafdbad256a89cdfd5dd5e4d45f74a981506e73ff74811740d206c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768179/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768179/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53770,53772</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22086522$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19675139$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>SCHLOTTERER, Andreas</creatorcontrib><creatorcontrib>KUKUDOV, Georgi</creatorcontrib><creatorcontrib>SAYED, Ahmed</creatorcontrib><creatorcontrib>FLEMING, Thomas</creatorcontrib><creatorcontrib>HUMPERT, Per</creatorcontrib><creatorcontrib>SCHWENGER, Vedat</creatorcontrib><creatorcontrib>ZEIER, Martin</creatorcontrib><creatorcontrib>HAMANN, Andreas</creatorcontrib><creatorcontrib>STERN, David</creatorcontrib><creatorcontrib>BROWNLEE, Michael</creatorcontrib><creatorcontrib>BIERHAUS, Angelika</creatorcontrib><creatorcontrib>NAWROTH, Peter</creatorcontrib><creatorcontrib>BOZORGMEHR, Farastuk</creatorcontrib><creatorcontrib>MORCOS, Michael</creatorcontrib><creatorcontrib>HUTTER, Harald</creatorcontrib><creatorcontrib>XUELIANG DU</creatorcontrib><creatorcontrib>OIKONOMOU, Dimitrios</creatorcontrib><creatorcontrib>IBRAHIM, Youssef</creatorcontrib><creatorcontrib>PFISTERER, Friederike</creatorcontrib><creatorcontrib>RABBANI, Naila</creatorcontrib><creatorcontrib>THORNALLEY, Paul</creatorcontrib><title>C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction
Andreas Schlotterer 1 ,
Georgi Kukudov 1 ,
Farastuk Bozorgmehr 1 ,
Harald Hutter 2 ,
Xueliang Du 3 ,
Dimitrios Oikonomou 1 ,
Youssef Ibrahim 1 ,
Friederike Pfisterer 1 ,
Naila Rabbani 4 ,
Paul Thornalley 4 ,
Ahmed Sayed 1 ,
Thomas Fleming 1 ,
Per Humpert 1 ,
Vedat Schwenger 1 ,
Martin Zeier 1 ,
Andreas Hamann 1 , 5 ,
David Stern 6 ,
Michael Brownlee 3 ,
Angelika Bierhaus 1 ,
Peter Nawroth 1 and
Michael Morcos 1
1 Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany;
2 Simon Fraser University, Department of Biological Sciences, Burnaby, Canada;
3 Departments of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York;
4 Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry, U.K.;
5 Diabetes-Clinic, Center for Vascular Medicine, Bad Nauheim, Germany;
6 College of Medicine, University of Cincinnati, Cincinnati, Ohio.
Corresponding author: Andreas Schlotterer, andreas.schlotterer{at}med.uni-heidelberg.de .
A.S., G.K., and F.B. contributed equally to this study.
Abstract
OBJECTIVE Establishing Caenorhabditis elegans as a model for glucose toxicity–mediated life span reduction.
RESEARCH DESIGN AND METHODS C. elegans were maintained to achieve glucose concentrations resembling the hyperglycemic conditions in diabetic patients. The effects
of high glucose on life span, glyoxalase-1 activity, advanced glycation end products (AGEs), and reactive oxygen species (ROS)
formation and on mitochondrial function were studied.
RESULTS High glucose conditions reduced mean life span from 18.5 ± 0.4 to 16.5 ± 0.6 days and maximum life span from 25.9 ± 0.4 to
23.2 ± 0.4 days, independent of glucose effects on cuticle or bacterial metabolization of glucose. The formation of methylglyoxal-modified
mitochondrial proteins and ROS was significantly increased by high glucose conditions and reduced by mitochondrial uncoupling
and complex IIIQo inhibition. Overexpression of the methylglyoxal–detoxifying enzyme glyoxalase-1 attenuated the life-shortening
effect of glucose by reducing AGE accumulation (by 65%) and ROS formation (by 50%) and restored mean (16.5 ± 0.6 to 20.6 ±
0.4 days) and maximum life span (23.2 ± 0.4 to 27.7 ± 2.3 days). In contrast, inhibition of glyoxalase-1 by RNAi further reduced
mean (16.5 ± 0.6 to 13.9 ± 0.7 days) and maximum life span (23.2 ± 0.4 to 20.3 ± 1.1 days). The life span reduction by glyoxalase-1
inhibition was independent from the insulin signaling pathway because high glucose conditions also affected daf-2 knockdown
animals in a similar manner.
CONCLUSIONS C. elegans is a suitable model organism to study glucose toxicity, in which high glucose conditions limit the life span by increasing
ROS formation and AGE modification of mitochondrial proteins in a daf-2 independent manner. Most importantly, glucose toxicity
can be prevented by improving glyoxalase-1–dependent methylglyoxal detoxification or preventing mitochondrial dysfunction.
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received April 22, 2009.
Accepted July 22, 2009.
© 2009 American Diabetes Association</description><subject>Age</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Caenorhabditis elegans</subject><subject>Caenorhabditis elegans - growth & development</subject><subject>Caenorhabditis elegans - metabolism</subject><subject>Caenorhabditis elegans - ultrastructure</subject><subject>Dextrose</subject><subject>Diabetes</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Diabetics</subject><subject>Disease Models, Animal</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Enzymes</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Glucose</subject><subject>Glucose - toxicity</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Hyperglycemia - metabolism</subject><subject>Life Expectancy - trends</subject><subject>Life span (Biology)</subject><subject>Life spans (Biology)</subject><subject>Longevity - physiology</subject><subject>Medical sciences</subject><subject>Metabolism</subject><subject>Microscopy, Electron, Scanning</subject><subject>Mitochondria - metabolism</subject><subject>Nematodes</subject><subject>Original</subject><subject>Physiological aspects</subject><subject>Proteins</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Research design</subject><subject>Toxicity</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp9kt-KEzEUxoMobrd64QtIULwQnJpkJsnMjbAU7QpdFv-BdyFNTqZZppPuZMZ173wH39AnMaXDroUiuUhy8jtfDud8CD2jZMbyXL61K1JlhAv5AE1olVdZzuT3h2hCCGUZlZU8QacxXhFCRFqP0QmthOQ0rybo03yGoYFatxHriC-ChQa70OF-DfhLP9hbHBw-9_UaL5rBhAh_fv3GF2C97sHipXcJ2-oWfwY7mN6H9gl65HQT4em4T9G3D--_zs-z5eXi4_xsmRlJaZ8xmuuyckSUTju70pZxkQLGOsut5VDYgjtZ6KqknAiQuUu3klJZEMuIMPkUvdvrbofVBqyBtu90o7ad3-juVgXt1eFL69eqDj8Uk6JMTUkCL0aBLlwPEHt1FYauTTUrRkVRVjzVOEUv91CtG1C-dSFpmY2PRp0xSkVOJZeJyo5QNbSQPg4tOJ_CB_zsCJ-WhY03RxNeHyQkpoeffa2HGFW5WP6vmJE1oUlzBpWGML88qm26EGMH7q6HlKidv9TOX2rnr8Q-_7fp9-RoqAS8GgEdjW5cp1vj4x3HGCkFZyxxb_bcOlnrxnegkqNW0EO8P_BSUapYwUn-Fy4L4vk</recordid><startdate>20091101</startdate><enddate>20091101</enddate><creator>SCHLOTTERER, Andreas</creator><creator>KUKUDOV, Georgi</creator><creator>SAYED, Ahmed</creator><creator>FLEMING, Thomas</creator><creator>HUMPERT, Per</creator><creator>SCHWENGER, Vedat</creator><creator>ZEIER, Martin</creator><creator>HAMANN, Andreas</creator><creator>STERN, David</creator><creator>BROWNLEE, Michael</creator><creator>BIERHAUS, Angelika</creator><creator>NAWROTH, Peter</creator><creator>BOZORGMEHR, Farastuk</creator><creator>MORCOS, Michael</creator><creator>HUTTER, Harald</creator><creator>XUELIANG DU</creator><creator>OIKONOMOU, Dimitrios</creator><creator>IBRAHIM, Youssef</creator><creator>PFISTERER, Friederike</creator><creator>RABBANI, Naila</creator><creator>THORNALLEY, Paul</creator><general>American Diabetes Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8GL</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>5PM</scope></search><sort><creationdate>20091101</creationdate><title>C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction</title><author>SCHLOTTERER, Andreas ; KUKUDOV, Georgi ; SAYED, Ahmed ; FLEMING, Thomas ; HUMPERT, Per ; SCHWENGER, Vedat ; ZEIER, Martin ; HAMANN, Andreas ; STERN, David ; BROWNLEE, Michael ; BIERHAUS, Angelika ; NAWROTH, Peter ; BOZORGMEHR, Farastuk ; MORCOS, Michael ; HUTTER, Harald ; XUELIANG DU ; OIKONOMOU, Dimitrios ; IBRAHIM, Youssef ; PFISTERER, Friederike ; RABBANI, Naila ; THORNALLEY, Paul</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c711t-213a89f068fafdbad256a89cdfd5dd5e4d45f74a981506e73ff74811740d206c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Age</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Caenorhabditis elegans</topic><topic>Caenorhabditis elegans - growth & development</topic><topic>Caenorhabditis elegans - metabolism</topic><topic>Caenorhabditis elegans - ultrastructure</topic><topic>Dextrose</topic><topic>Diabetes</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Diabetics</topic><topic>Disease Models, Animal</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Enzymes</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Glucose</topic><topic>Glucose - toxicity</topic><topic>Health aspects</topic><topic>Humans</topic><topic>Hyperglycemia - metabolism</topic><topic>Life Expectancy - trends</topic><topic>Life span (Biology)</topic><topic>Life spans (Biology)</topic><topic>Longevity - physiology</topic><topic>Medical sciences</topic><topic>Metabolism</topic><topic>Microscopy, Electron, Scanning</topic><topic>Mitochondria - metabolism</topic><topic>Nematodes</topic><topic>Original</topic><topic>Physiological aspects</topic><topic>Proteins</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Research design</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>SCHLOTTERER, Andreas</creatorcontrib><creatorcontrib>KUKUDOV, Georgi</creatorcontrib><creatorcontrib>SAYED, Ahmed</creatorcontrib><creatorcontrib>FLEMING, Thomas</creatorcontrib><creatorcontrib>HUMPERT, Per</creatorcontrib><creatorcontrib>SCHWENGER, Vedat</creatorcontrib><creatorcontrib>ZEIER, Martin</creatorcontrib><creatorcontrib>HAMANN, Andreas</creatorcontrib><creatorcontrib>STERN, David</creatorcontrib><creatorcontrib>BROWNLEE, Michael</creatorcontrib><creatorcontrib>BIERHAUS, Angelika</creatorcontrib><creatorcontrib>NAWROTH, Peter</creatorcontrib><creatorcontrib>BOZORGMEHR, Farastuk</creatorcontrib><creatorcontrib>MORCOS, Michael</creatorcontrib><creatorcontrib>HUTTER, Harald</creatorcontrib><creatorcontrib>XUELIANG DU</creatorcontrib><creatorcontrib>OIKONOMOU, Dimitrios</creatorcontrib><creatorcontrib>IBRAHIM, Youssef</creatorcontrib><creatorcontrib>PFISTERER, Friederike</creatorcontrib><creatorcontrib>RABBANI, Naila</creatorcontrib><creatorcontrib>THORNALLEY, Paul</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>SCHLOTTERER, Andreas</au><au>KUKUDOV, Georgi</au><au>SAYED, Ahmed</au><au>FLEMING, Thomas</au><au>HUMPERT, Per</au><au>SCHWENGER, Vedat</au><au>ZEIER, Martin</au><au>HAMANN, Andreas</au><au>STERN, David</au><au>BROWNLEE, Michael</au><au>BIERHAUS, Angelika</au><au>NAWROTH, Peter</au><au>BOZORGMEHR, Farastuk</au><au>MORCOS, Michael</au><au>HUTTER, Harald</au><au>XUELIANG DU</au><au>OIKONOMOU, Dimitrios</au><au>IBRAHIM, Youssef</au><au>PFISTERER, Friederike</au><au>RABBANI, Naila</au><au>THORNALLEY, Paul</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2009-11-01</date><risdate>2009</risdate><volume>58</volume><issue>11</issue><spage>2450</spage><epage>2456</epage><pages>2450-2456</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction
Andreas Schlotterer 1 ,
Georgi Kukudov 1 ,
Farastuk Bozorgmehr 1 ,
Harald Hutter 2 ,
Xueliang Du 3 ,
Dimitrios Oikonomou 1 ,
Youssef Ibrahim 1 ,
Friederike Pfisterer 1 ,
Naila Rabbani 4 ,
Paul Thornalley 4 ,
Ahmed Sayed 1 ,
Thomas Fleming 1 ,
Per Humpert 1 ,
Vedat Schwenger 1 ,
Martin Zeier 1 ,
Andreas Hamann 1 , 5 ,
David Stern 6 ,
Michael Brownlee 3 ,
Angelika Bierhaus 1 ,
Peter Nawroth 1 and
Michael Morcos 1
1 Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany;
2 Simon Fraser University, Department of Biological Sciences, Burnaby, Canada;
3 Departments of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York;
4 Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry, U.K.;
5 Diabetes-Clinic, Center for Vascular Medicine, Bad Nauheim, Germany;
6 College of Medicine, University of Cincinnati, Cincinnati, Ohio.
Corresponding author: Andreas Schlotterer, andreas.schlotterer{at}med.uni-heidelberg.de .
A.S., G.K., and F.B. contributed equally to this study.
Abstract
OBJECTIVE Establishing Caenorhabditis elegans as a model for glucose toxicity–mediated life span reduction.
RESEARCH DESIGN AND METHODS C. elegans were maintained to achieve glucose concentrations resembling the hyperglycemic conditions in diabetic patients. The effects
of high glucose on life span, glyoxalase-1 activity, advanced glycation end products (AGEs), and reactive oxygen species (ROS)
formation and on mitochondrial function were studied.
RESULTS High glucose conditions reduced mean life span from 18.5 ± 0.4 to 16.5 ± 0.6 days and maximum life span from 25.9 ± 0.4 to
23.2 ± 0.4 days, independent of glucose effects on cuticle or bacterial metabolization of glucose. The formation of methylglyoxal-modified
mitochondrial proteins and ROS was significantly increased by high glucose conditions and reduced by mitochondrial uncoupling
and complex IIIQo inhibition. Overexpression of the methylglyoxal–detoxifying enzyme glyoxalase-1 attenuated the life-shortening
effect of glucose by reducing AGE accumulation (by 65%) and ROS formation (by 50%) and restored mean (16.5 ± 0.6 to 20.6 ±
0.4 days) and maximum life span (23.2 ± 0.4 to 27.7 ± 2.3 days). In contrast, inhibition of glyoxalase-1 by RNAi further reduced
mean (16.5 ± 0.6 to 13.9 ± 0.7 days) and maximum life span (23.2 ± 0.4 to 20.3 ± 1.1 days). The life span reduction by glyoxalase-1
inhibition was independent from the insulin signaling pathway because high glucose conditions also affected daf-2 knockdown
animals in a similar manner.
CONCLUSIONS C. elegans is a suitable model organism to study glucose toxicity, in which high glucose conditions limit the life span by increasing
ROS formation and AGE modification of mitochondrial proteins in a daf-2 independent manner. Most importantly, glucose toxicity
can be prevented by improving glyoxalase-1–dependent methylglyoxal detoxification or preventing mitochondrial dysfunction.
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received April 22, 2009.
Accepted July 22, 2009.
© 2009 American Diabetes Association</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>19675139</pmid><doi>10.2337/db09-0567</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2009-11, Vol.58 (11), p.2450-2456 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_gale_infotracgeneralonefile_A211631757 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Age Animals Biological and medical sciences Caenorhabditis elegans Caenorhabditis elegans - growth & development Caenorhabditis elegans - metabolism Caenorhabditis elegans - ultrastructure Dextrose Diabetes Diabetes. Impaired glucose tolerance Diabetics Disease Models, Animal Endocrine pancreas. Apud cells (diseases) Endocrinopathies Enzymes Etiopathogenesis. Screening. Investigations. Target tissue resistance Glucose Glucose - toxicity Health aspects Humans Hyperglycemia - metabolism Life Expectancy - trends Life span (Biology) Life spans (Biology) Longevity - physiology Medical sciences Metabolism Microscopy, Electron, Scanning Mitochondria - metabolism Nematodes Original Physiological aspects Proteins Reactive Oxygen Species - metabolism Research design Toxicity |
| title | C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction |
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