Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats
Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats Yun-Ping Zhou 1 , Azadeh Madjidi 1 , Maria E. Wilson 1 , David A. Nothhelfer 1 , John H. Johnson 2 , John F. Palma 1 , Anthony Schweitzer 1 , Charles Burant 2 , John E. Blume 1 and Jeffrey D. Johnson 1 1 Meta...
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| creator | ZHOU, Yim-Ping MADJIDI, Azadeh WILSON, Maria E NOTHHELFER, David A JOHNSON, John H PALMA, John F SCHWEITZER, Anthony BURANT, Charles BLUME, John E JOHNSON, Jeffrey D |
| description | Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats
Yun-Ping Zhou 1 ,
Azadeh Madjidi 1 ,
Maria E. Wilson 1 ,
David A. Nothhelfer 1 ,
John H. Johnson 2 ,
John F. Palma 1 ,
Anthony Schweitzer 1 ,
Charles Burant 2 ,
John E. Blume 1 and
Jeffrey D. Johnson 1
1 Metabolex, Hayward, California
2 Pfizer Global Research and Development, Ann Arbor, Michigan
Address correspondence and reprint requests to Dr. Jeffrey D. Johnson, Metabolex, 3876 Bay Center Place, Hayward, CA 94583.
E-mail: jjohnson{at}metabolex.com
Abstract
To assess the molecular changes associated with pancreatic β-cell dysfunction occurring during the onset of type 2 diabetes,
we profiled pancreatic islet mRNAs from diabetic male and high-fat–fed female Zucker diabetic fatty (ZDF) rats and their nondiabetic
lean counterparts on custom islet-specific oligonucleotide arrays. The most prominent changes in both the male and female
models of type 2 diabetes were increases in the mRNAs encoding proteases and extracellular matrix components that are associated
with tissue remodeling and fibrosis. The mRNAs for metalloproteinase (MMP)-2, -12, and -14 were sharply increased with the
onset of islet dysfunction and diabetes. Zymography of islet extracts revealed a concurrent, >10-fold increase in MMP-2 protease
activity in islets from 9-week-old male ZDF rats. Treatment of female ZDF rats receiving a diabetogenic diet with PD166793,
a broad-spectrum MMP inhibitor, substantially prevented diabetes. The effect of this compound was due in part to marked β-cell
expansion. These studies indicate that MMPs contribute to islet fibrosis and insulin insufficiency in ZDF rats. Class-targeted
protease inhibitors should be explored for their potential therapeutic utility in preservation of β-cell mass in type 2 diabetes.
ECM, extracellular matrix
IPGTT, intraperitoneal glucose tolerance test
MMP, metalloproteinase
Footnotes
Y.-P.Z. is currently affiliated with Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey. J.F.P. and J.E.B.
are currently affiliated with Affymetrix, Santa Clara, California. C.B. is currently affiliated with the Department of Medicine,
University of Michigan, Ann Arbor, Michigan.
C.B. has been on advisory boards for Takeda and has received consulting fees from Takeda, Concurrent, and Sankyo.
Accepted June 20, 2005.
Received October 21, 2004.
DIABETES |
| doi_str_mv | 10.2337/diabetes.54.9.2612 |
| format | Article |
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Yun-Ping Zhou 1 ,
Azadeh Madjidi 1 ,
Maria E. Wilson 1 ,
David A. Nothhelfer 1 ,
John H. Johnson 2 ,
John F. Palma 1 ,
Anthony Schweitzer 1 ,
Charles Burant 2 ,
John E. Blume 1 and
Jeffrey D. Johnson 1
1 Metabolex, Hayward, California
2 Pfizer Global Research and Development, Ann Arbor, Michigan
Address correspondence and reprint requests to Dr. Jeffrey D. Johnson, Metabolex, 3876 Bay Center Place, Hayward, CA 94583.
E-mail: jjohnson{at}metabolex.com
Abstract
To assess the molecular changes associated with pancreatic β-cell dysfunction occurring during the onset of type 2 diabetes,
we profiled pancreatic islet mRNAs from diabetic male and high-fat–fed female Zucker diabetic fatty (ZDF) rats and their nondiabetic
lean counterparts on custom islet-specific oligonucleotide arrays. The most prominent changes in both the male and female
models of type 2 diabetes were increases in the mRNAs encoding proteases and extracellular matrix components that are associated
with tissue remodeling and fibrosis. The mRNAs for metalloproteinase (MMP)-2, -12, and -14 were sharply increased with the
onset of islet dysfunction and diabetes. Zymography of islet extracts revealed a concurrent, >10-fold increase in MMP-2 protease
activity in islets from 9-week-old male ZDF rats. Treatment of female ZDF rats receiving a diabetogenic diet with PD166793,
a broad-spectrum MMP inhibitor, substantially prevented diabetes. The effect of this compound was due in part to marked β-cell
expansion. These studies indicate that MMPs contribute to islet fibrosis and insulin insufficiency in ZDF rats. Class-targeted
protease inhibitors should be explored for their potential therapeutic utility in preservation of β-cell mass in type 2 diabetes.
ECM, extracellular matrix
IPGTT, intraperitoneal glucose tolerance test
MMP, metalloproteinase
Footnotes
Y.-P.Z. is currently affiliated with Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey. J.F.P. and J.E.B.
are currently affiliated with Affymetrix, Santa Clara, California. C.B. is currently affiliated with the Department of Medicine,
University of Michigan, Ann Arbor, Michigan.
C.B. has been on advisory boards for Takeda and has received consulting fees from Takeda, Concurrent, and Sankyo.
Accepted June 20, 2005.
Received October 21, 2004.
DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/diabetes.54.9.2612</identifier><identifier>PMID: 16123349</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Animals ; Apoptosis ; Arrays ; Biological and medical sciences ; Diabetes ; Diabetes. Impaired glucose tolerance ; Dietary Fats - metabolism ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Enzymes ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Extracellular matrix ; Female ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation ; Glucose ; Hybridization ; Hydroxamic Acids - pharmacology ; Hyperglycemia ; Insulin - physiology ; Insulin resistance ; Islets of Langerhans - drug effects ; Islets of Langerhans - physiology ; Laboratory animals ; Male ; Matrix Metalloproteinase Inhibitors ; Matrix Metalloproteinases - metabolism ; Measurement ; Medical sciences ; Observations ; Oligopeptides - pharmacology ; Rats ; Rats, Zucker ; RNA, Messenger - metabolism ; Time Factors ; Type 2 diabetes ; Up-Regulation</subject><ispartof>Diabetes (New York, N.Y.), 2005-09, Vol.54 (9), p.2612-2619</ispartof><rights>2005 INIST-CNRS</rights><rights>COPYRIGHT 2005 American Diabetes Association</rights><rights>COPYRIGHT 2005 American Diabetes Association</rights><rights>Copyright American Diabetes Association Sep 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c653t-294893eb0a0dc25ee142f2a661a41b85aab59b9ff730c55c1b2e416a3d9eda923</citedby><cites>FETCH-LOGICAL-c653t-294893eb0a0dc25ee142f2a661a41b85aab59b9ff730c55c1b2e416a3d9eda923</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17075820$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16123349$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ZHOU, Yim-Ping</creatorcontrib><creatorcontrib>MADJIDI, Azadeh</creatorcontrib><creatorcontrib>WILSON, Maria E</creatorcontrib><creatorcontrib>NOTHHELFER, David A</creatorcontrib><creatorcontrib>JOHNSON, John H</creatorcontrib><creatorcontrib>PALMA, John F</creatorcontrib><creatorcontrib>SCHWEITZER, Anthony</creatorcontrib><creatorcontrib>BURANT, Charles</creatorcontrib><creatorcontrib>BLUME, John E</creatorcontrib><creatorcontrib>JOHNSON, Jeffrey D</creatorcontrib><title>Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats
Yun-Ping Zhou 1 ,
Azadeh Madjidi 1 ,
Maria E. Wilson 1 ,
David A. Nothhelfer 1 ,
John H. Johnson 2 ,
John F. Palma 1 ,
Anthony Schweitzer 1 ,
Charles Burant 2 ,
John E. Blume 1 and
Jeffrey D. Johnson 1
1 Metabolex, Hayward, California
2 Pfizer Global Research and Development, Ann Arbor, Michigan
Address correspondence and reprint requests to Dr. Jeffrey D. Johnson, Metabolex, 3876 Bay Center Place, Hayward, CA 94583.
E-mail: jjohnson{at}metabolex.com
Abstract
To assess the molecular changes associated with pancreatic β-cell dysfunction occurring during the onset of type 2 diabetes,
we profiled pancreatic islet mRNAs from diabetic male and high-fat–fed female Zucker diabetic fatty (ZDF) rats and their nondiabetic
lean counterparts on custom islet-specific oligonucleotide arrays. The most prominent changes in both the male and female
models of type 2 diabetes were increases in the mRNAs encoding proteases and extracellular matrix components that are associated
with tissue remodeling and fibrosis. The mRNAs for metalloproteinase (MMP)-2, -12, and -14 were sharply increased with the
onset of islet dysfunction and diabetes. Zymography of islet extracts revealed a concurrent, >10-fold increase in MMP-2 protease
activity in islets from 9-week-old male ZDF rats. Treatment of female ZDF rats receiving a diabetogenic diet with PD166793,
a broad-spectrum MMP inhibitor, substantially prevented diabetes. The effect of this compound was due in part to marked β-cell
expansion. These studies indicate that MMPs contribute to islet fibrosis and insulin insufficiency in ZDF rats. Class-targeted
protease inhibitors should be explored for their potential therapeutic utility in preservation of β-cell mass in type 2 diabetes.
ECM, extracellular matrix
IPGTT, intraperitoneal glucose tolerance test
MMP, metalloproteinase
Footnotes
Y.-P.Z. is currently affiliated with Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey. J.F.P. and J.E.B.
are currently affiliated with Affymetrix, Santa Clara, California. C.B. is currently affiliated with the Department of Medicine,
University of Michigan, Ann Arbor, Michigan.
C.B. has been on advisory boards for Takeda and has received consulting fees from Takeda, Concurrent, and Sankyo.
Accepted June 20, 2005.
Received October 21, 2004.
DIABETES</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Arrays</subject><subject>Biological and medical sciences</subject><subject>Diabetes</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Dietary Fats - metabolism</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Enzymes</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Extracellular matrix</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation</subject><subject>Glucose</subject><subject>Hybridization</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Hyperglycemia</subject><subject>Insulin - physiology</subject><subject>Insulin resistance</subject><subject>Islets of Langerhans - drug effects</subject><subject>Islets of Langerhans - physiology</subject><subject>Laboratory animals</subject><subject>Male</subject><subject>Matrix Metalloproteinase Inhibitors</subject><subject>Matrix Metalloproteinases - metabolism</subject><subject>Measurement</subject><subject>Medical sciences</subject><subject>Observations</subject><subject>Oligopeptides - pharmacology</subject><subject>Rats</subject><subject>Rats, Zucker</subject><subject>RNA, Messenger - metabolism</subject><subject>Time Factors</subject><subject>Type 2 diabetes</subject><subject>Up-Regulation</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpt0l-L1DAQAPAiireefgEfpAgKIq3507TN47F658EeB6Ig-hCm6XQvZzY9kxRvv73Z25VlZZmHwOQ3yTBMlr2kpGScNx96Ax1GDKWoSlmymrJH2YxKLgvOmu-PsxkhlBW0kc1J9iyEW0JIneJpdkKT5bySs-znFURv7vMrjGDteOfHiMZBwJDPR5euuiliHsf80oXJGvdwDoPRBp1e5ynxY9K_0OcfH5oxOj-HGNf5F4jhefZkABvwxe48zb6df_o6_1wsri8u52eLQteCx4LJqpUcOwKk10wg0ooNDOqaQkW7VgB0QnZyGBpOtBCadgwrWgPvJfYgGT_N3m7fTd3_njBEtTJBo7XgcJyCqltBWyY28PV_8HacvEu9KUbrSrIEEyq2aAkWlXHDGD3oJTr0YEeHg0npM8rTCNN86-TLIz5Fjyujjxa8OyhIJuJ9XMIUgmovFoe2OGb1aC0uUaUxzq8PPdt67ccQPA7qzpsV-LWiRG2WRv1bGiUqJdVmaVLRq91Ypm6F_b5ktyUJvNkBCBrs4MFpE_auIY1oGUnu_dbdmOXNH-Nx_9uRb_8CeizY1g</recordid><startdate>20050901</startdate><enddate>20050901</enddate><creator>ZHOU, Yim-Ping</creator><creator>MADJIDI, Azadeh</creator><creator>WILSON, Maria E</creator><creator>NOTHHELFER, David A</creator><creator>JOHNSON, John H</creator><creator>PALMA, John F</creator><creator>SCHWEITZER, Anthony</creator><creator>BURANT, Charles</creator><creator>BLUME, John E</creator><creator>JOHNSON, Jeffrey D</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>7X8</scope></search><sort><creationdate>20050901</creationdate><title>Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats</title><author>ZHOU, Yim-Ping ; MADJIDI, Azadeh ; WILSON, Maria E ; NOTHHELFER, David A ; JOHNSON, John H ; PALMA, John F ; SCHWEITZER, Anthony ; BURANT, Charles ; BLUME, John E ; JOHNSON, Jeffrey D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c653t-294893eb0a0dc25ee142f2a661a41b85aab59b9ff730c55c1b2e416a3d9eda923</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Arrays</topic><topic>Biological and medical sciences</topic><topic>Diabetes</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Dietary Fats - metabolism</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Enzymes</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Extracellular matrix</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation</topic><topic>Glucose</topic><topic>Hybridization</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Hyperglycemia</topic><topic>Insulin - physiology</topic><topic>Insulin resistance</topic><topic>Islets of Langerhans - drug effects</topic><topic>Islets of Langerhans - physiology</topic><topic>Laboratory animals</topic><topic>Male</topic><topic>Matrix Metalloproteinase Inhibitors</topic><topic>Matrix Metalloproteinases - metabolism</topic><topic>Measurement</topic><topic>Medical sciences</topic><topic>Observations</topic><topic>Oligopeptides - pharmacology</topic><topic>Rats</topic><topic>Rats, Zucker</topic><topic>RNA, Messenger - metabolism</topic><topic>Time Factors</topic><topic>Type 2 diabetes</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>ZHOU, Yim-Ping</creatorcontrib><creatorcontrib>MADJIDI, Azadeh</creatorcontrib><creatorcontrib>WILSON, Maria E</creatorcontrib><creatorcontrib>NOTHHELFER, David A</creatorcontrib><creatorcontrib>JOHNSON, John H</creatorcontrib><creatorcontrib>PALMA, John F</creatorcontrib><creatorcontrib>SCHWEITZER, Anthony</creatorcontrib><creatorcontrib>BURANT, Charles</creatorcontrib><creatorcontrib>BLUME, John E</creatorcontrib><creatorcontrib>JOHNSON, Jeffrey D</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: High School</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database (Alumni Edition)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>ProQuest Biological Science Collection</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>ZHOU, Yim-Ping</au><au>MADJIDI, Azadeh</au><au>WILSON, Maria E</au><au>NOTHHELFER, David A</au><au>JOHNSON, John H</au><au>PALMA, John F</au><au>SCHWEITZER, Anthony</au><au>BURANT, Charles</au><au>BLUME, John E</au><au>JOHNSON, Jeffrey D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2005-09-01</date><risdate>2005</risdate><volume>54</volume><issue>9</issue><spage>2612</spage><epage>2619</epage><pages>2612-2619</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats
Yun-Ping Zhou 1 ,
Azadeh Madjidi 1 ,
Maria E. Wilson 1 ,
David A. Nothhelfer 1 ,
John H. Johnson 2 ,
John F. Palma 1 ,
Anthony Schweitzer 1 ,
Charles Burant 2 ,
John E. Blume 1 and
Jeffrey D. Johnson 1
1 Metabolex, Hayward, California
2 Pfizer Global Research and Development, Ann Arbor, Michigan
Address correspondence and reprint requests to Dr. Jeffrey D. Johnson, Metabolex, 3876 Bay Center Place, Hayward, CA 94583.
E-mail: jjohnson{at}metabolex.com
Abstract
To assess the molecular changes associated with pancreatic β-cell dysfunction occurring during the onset of type 2 diabetes,
we profiled pancreatic islet mRNAs from diabetic male and high-fat–fed female Zucker diabetic fatty (ZDF) rats and their nondiabetic
lean counterparts on custom islet-specific oligonucleotide arrays. The most prominent changes in both the male and female
models of type 2 diabetes were increases in the mRNAs encoding proteases and extracellular matrix components that are associated
with tissue remodeling and fibrosis. The mRNAs for metalloproteinase (MMP)-2, -12, and -14 were sharply increased with the
onset of islet dysfunction and diabetes. Zymography of islet extracts revealed a concurrent, >10-fold increase in MMP-2 protease
activity in islets from 9-week-old male ZDF rats. Treatment of female ZDF rats receiving a diabetogenic diet with PD166793,
a broad-spectrum MMP inhibitor, substantially prevented diabetes. The effect of this compound was due in part to marked β-cell
expansion. These studies indicate that MMPs contribute to islet fibrosis and insulin insufficiency in ZDF rats. Class-targeted
protease inhibitors should be explored for their potential therapeutic utility in preservation of β-cell mass in type 2 diabetes.
ECM, extracellular matrix
IPGTT, intraperitoneal glucose tolerance test
MMP, metalloproteinase
Footnotes
Y.-P.Z. is currently affiliated with Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey. J.F.P. and J.E.B.
are currently affiliated with Affymetrix, Santa Clara, California. C.B. is currently affiliated with the Department of Medicine,
University of Michigan, Ann Arbor, Michigan.
C.B. has been on advisory boards for Takeda and has received consulting fees from Takeda, Concurrent, and Sankyo.
Accepted June 20, 2005.
Received October 21, 2004.
DIABETES</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>16123349</pmid><doi>10.2337/diabetes.54.9.2612</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2005-09, Vol.54 (9), p.2612-2619 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_gale_incontextgauss_8GL_A136120016 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Animals Apoptosis Arrays Biological and medical sciences Diabetes Diabetes. Impaired glucose tolerance Dietary Fats - metabolism Endocrine pancreas. Apud cells (diseases) Endocrinopathies Enzymes Etiopathogenesis. Screening. Investigations. Target tissue resistance Extracellular matrix Female Gene expression Gene Expression Profiling Gene Expression Regulation Glucose Hybridization Hydroxamic Acids - pharmacology Hyperglycemia Insulin - physiology Insulin resistance Islets of Langerhans - drug effects Islets of Langerhans - physiology Laboratory animals Male Matrix Metalloproteinase Inhibitors Matrix Metalloproteinases - metabolism Measurement Medical sciences Observations Oligopeptides - pharmacology Rats Rats, Zucker RNA, Messenger - metabolism Time Factors Type 2 diabetes Up-Regulation |
| title | Matrix Metalloproteinases Contribute to Insulin Insufficiency in Zucker Diabetic Fatty Rats |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T00%3A03%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pasca&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Matrix%20Metalloproteinases%20Contribute%20to%20Insulin%20Insufficiency%20in%20Zucker%20Diabetic%20Fatty%20Rats&rft.jtitle=Diabetes%20(New%20York,%20N.Y.)&rft.au=ZHOU,%20Yim-Ping&rft.date=2005-09-01&rft.volume=54&rft.issue=9&rft.spage=2612&rft.epage=2619&rft.pages=2612-2619&rft.issn=0012-1797&rft.eissn=1939-327X&rft.coden=DIAEAZ&rft_id=info:doi/10.2337/diabetes.54.9.2612&rft_dat=%3Cgale_pasca%3EA136120016%3C/gale_pasca%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=216492851&rft_id=info:pmid/16123349&rft_galeid=A136120016&rfr_iscdi=true |