Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart
Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart Luigi Laviola 1 , Gaetana Belsanti 1 , Alberto M. Davalli 2 , Raffaele Napoli 2 , Sebastio Perrini 1 , Gordon C. Weir 2 , Riccardo Giorgino 1 and Francesco Giorgino 1 1 Internal...
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| Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2001-12, Vol.50 (12), p.2709-2720 |
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| creator | LAVIOLA, Luigi BELSANTI, Gaetana DAVALLI, Alberto M NAPOLI, Raffaele PERRINI, Sebastio WEIR, Gordon C GIORGINO, Riccardo GIORGINO, Francesco |
| description | Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart
Luigi Laviola 1 ,
Gaetana Belsanti 1 ,
Alberto M. Davalli 2 ,
Raffaele Napoli 2 ,
Sebastio Perrini 1 ,
Gordon C. Weir 2 ,
Riccardo Giorgino 1 and
Francesco Giorgino 1
1 Internal Medicine, Endocrinology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of
Bari, Bari, Italy
2 Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
Abstract
The insulin signaling cascade was investigated in rat myocardium in vivo in the presence of streptozocin (STZ)-induced diabetes
and after diabetes treatment by islet transplantation under the kidney capsule. The levels of insulin-stimulated tyrosine
phosphorylation of the insulin receptor β-subunit, insulin receptor substrate (IRS)-2, and p52 Shc were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. The amount
of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2
were also elevated in diabetes, whereas no changes in IRS-1–associated PI 3-kinase were observed. Insulin-induced phosphorylation
of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. In contrast
with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate
of Akt, was markedly reduced in diabetes. In islet-transplanted rats, the majority of the alterations in insulin-signaling
proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association
with PI 3-kinase was blunted. In conclusion, in the diabetic heart, 1 ) IRS-1, IRS-2, and p52 Shc are differently altered, 2 ) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3 ) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3.
Islet transplantation under the kidney capsule is a potentially effective therapy to correct several diabetes-induced abnormalities
of insulin signaling in cardiac muscle but does not restore the responsiveness of all signaling reactions to insulin.
Footnotes
Address correspondence and reprint requests to Francesco Giorgino, MD, PhD, Internal Medicine, Endocrinology and Metabolic
Diseases, Department of |
| doi_str_mv | 10.2337/diabetes.50.12.2709 |
| format | Article |
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Luigi Laviola 1 ,
Gaetana Belsanti 1 ,
Alberto M. Davalli 2 ,
Raffaele Napoli 2 ,
Sebastio Perrini 1 ,
Gordon C. Weir 2 ,
Riccardo Giorgino 1 and
Francesco Giorgino 1
1 Internal Medicine, Endocrinology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of
Bari, Bari, Italy
2 Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
Abstract
The insulin signaling cascade was investigated in rat myocardium in vivo in the presence of streptozocin (STZ)-induced diabetes
and after diabetes treatment by islet transplantation under the kidney capsule. The levels of insulin-stimulated tyrosine
phosphorylation of the insulin receptor β-subunit, insulin receptor substrate (IRS)-2, and p52 Shc were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. The amount
of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2
were also elevated in diabetes, whereas no changes in IRS-1–associated PI 3-kinase were observed. Insulin-induced phosphorylation
of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. In contrast
with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate
of Akt, was markedly reduced in diabetes. In islet-transplanted rats, the majority of the alterations in insulin-signaling
proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association
with PI 3-kinase was blunted. In conclusion, in the diabetic heart, 1 ) IRS-1, IRS-2, and p52 Shc are differently altered, 2 ) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3 ) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3.
Islet transplantation under the kidney capsule is a potentially effective therapy to correct several diabetes-induced abnormalities
of insulin signaling in cardiac muscle but does not restore the responsiveness of all signaling reactions to insulin.
Footnotes
Address correspondence and reprint requests to Francesco Giorgino, MD, PhD, Internal Medicine, Endocrinology and Metabolic
Diseases, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare, 11, I-70124 Bari, Italy.
E-mail: giorginf{at}tin.it .
Received for publication 22 December 2000 and accepted in revised form 16 August 2001.
A.M.D. is currently affiliated with the Scientific Institute H San Raffaele, Milan, Italy.
R.N. is currently affiliated with the Department of Internal Medicine, University of Naples Federico II, Naples, Italy.
BSA, bovine serum albumin; Erk, extracellular signal-regulated kinase; GSK, glycogen synthase kinase; IRS, insulin receptor
substrate; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; PBS, phosphate-buffered saline; PDK, phosphoinositide-dependent
kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PP1, protein phosphatase 1; STZ, streptozocin.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/diabetes.50.12.2709</identifier><identifier>PMID: 11723053</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Adaptor Proteins, Signal Transducing ; Adaptor Proteins, Vesicular Transport ; Animals ; Associated diseases and complications ; Biological and medical sciences ; Calcium-Calmodulin-Dependent Protein Kinases - metabolism ; Diabetes ; Diabetes Mellitus, Experimental - metabolism ; Diabetes Mellitus, Experimental - surgery ; Diabetes research ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Fatty acids ; Glucose ; Glycogen Synthase Kinase 3 ; Glycogen Synthase Kinases ; Health aspects ; Insulin ; Insulin - metabolism ; Insulin Receptor Substrate Proteins ; Intracellular Signaling Peptides and Proteins ; Islets of Langerhans Transplantation ; Kinases ; Male ; Medical sciences ; Mitogen-Activated Protein Kinase Kinases - metabolism ; Mitogen-Activated Protein Kinases - metabolism ; Myocardium - metabolism ; Oxidation ; Phosphatidylinositol 3-Kinases - metabolism ; Phosphoproteins - metabolism ; Phosphorylation ; Phosphoserine - metabolism ; Phosphotyrosine - metabolism ; Protein-Serine-Threonine Kinases ; Proteins ; Proteins - metabolism ; Proto-Oncogene Proteins - metabolism ; Proto-Oncogene Proteins c-akt ; Rats ; Rats, Inbred Lew ; Receptor, Insulin - metabolism ; Shc Signaling Adaptor Proteins ; Signal Transduction ; Src Homology 2 Domain-Containing, Transforming Protein 1 ; Streptozocin</subject><ispartof>Diabetes (New York, N.Y.), 2001-12, Vol.50 (12), p.2709-2720</ispartof><rights>2002 INIST-CNRS</rights><rights>COPYRIGHT 2001 American Diabetes Association</rights><rights>Copyright American Diabetes Association Dec 2001</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c589t-455d259e94b9dfe775faa913da98ced1b5f45963bf42640c74e1169fd1d1cca13</citedby><cites>FETCH-LOGICAL-c589t-455d259e94b9dfe775faa913da98ced1b5f45963bf42640c74e1169fd1d1cca13</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=14155484$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11723053$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LAVIOLA, Luigi</creatorcontrib><creatorcontrib>BELSANTI, Gaetana</creatorcontrib><creatorcontrib>DAVALLI, Alberto M</creatorcontrib><creatorcontrib>NAPOLI, Raffaele</creatorcontrib><creatorcontrib>PERRINI, Sebastio</creatorcontrib><creatorcontrib>WEIR, Gordon C</creatorcontrib><creatorcontrib>GIORGINO, Riccardo</creatorcontrib><creatorcontrib>GIORGINO, Francesco</creatorcontrib><title>Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart
Luigi Laviola 1 ,
Gaetana Belsanti 1 ,
Alberto M. Davalli 2 ,
Raffaele Napoli 2 ,
Sebastio Perrini 1 ,
Gordon C. Weir 2 ,
Riccardo Giorgino 1 and
Francesco Giorgino 1
1 Internal Medicine, Endocrinology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of
Bari, Bari, Italy
2 Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
Abstract
The insulin signaling cascade was investigated in rat myocardium in vivo in the presence of streptozocin (STZ)-induced diabetes
and after diabetes treatment by islet transplantation under the kidney capsule. The levels of insulin-stimulated tyrosine
phosphorylation of the insulin receptor β-subunit, insulin receptor substrate (IRS)-2, and p52 Shc were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. The amount
of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2
were also elevated in diabetes, whereas no changes in IRS-1–associated PI 3-kinase were observed. Insulin-induced phosphorylation
of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. In contrast
with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate
of Akt, was markedly reduced in diabetes. In islet-transplanted rats, the majority of the alterations in insulin-signaling
proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association
with PI 3-kinase was blunted. In conclusion, in the diabetic heart, 1 ) IRS-1, IRS-2, and p52 Shc are differently altered, 2 ) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3 ) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3.
Islet transplantation under the kidney capsule is a potentially effective therapy to correct several diabetes-induced abnormalities
of insulin signaling in cardiac muscle but does not restore the responsiveness of all signaling reactions to insulin.
Footnotes
Address correspondence and reprint requests to Francesco Giorgino, MD, PhD, Internal Medicine, Endocrinology and Metabolic
Diseases, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare, 11, I-70124 Bari, Italy.
E-mail: giorginf{at}tin.it .
Received for publication 22 December 2000 and accepted in revised form 16 August 2001.
A.M.D. is currently affiliated with the Scientific Institute H San Raffaele, Milan, Italy.
R.N. is currently affiliated with the Department of Internal Medicine, University of Naples Federico II, Naples, Italy.
BSA, bovine serum albumin; Erk, extracellular signal-regulated kinase; GSK, glycogen synthase kinase; IRS, insulin receptor
substrate; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; PBS, phosphate-buffered saline; PDK, phosphoinositide-dependent
kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PP1, protein phosphatase 1; STZ, streptozocin.</description><subject>Adaptor Proteins, Signal Transducing</subject><subject>Adaptor Proteins, Vesicular Transport</subject><subject>Animals</subject><subject>Associated diseases and complications</subject><subject>Biological and medical sciences</subject><subject>Calcium-Calmodulin-Dependent Protein Kinases - metabolism</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Experimental - metabolism</subject><subject>Diabetes Mellitus, Experimental - surgery</subject><subject>Diabetes research</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Fatty acids</subject><subject>Glucose</subject><subject>Glycogen Synthase Kinase 3</subject><subject>Glycogen Synthase Kinases</subject><subject>Health aspects</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin Receptor Substrate Proteins</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Islets of Langerhans Transplantation</subject><subject>Kinases</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mitogen-Activated Protein Kinase Kinases - metabolism</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Myocardium - metabolism</subject><subject>Oxidation</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation</subject><subject>Phosphoserine - metabolism</subject><subject>Phosphotyrosine - metabolism</subject><subject>Protein-Serine-Threonine Kinases</subject><subject>Proteins</subject><subject>Proteins - metabolism</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Proto-Oncogene Proteins c-akt</subject><subject>Rats</subject><subject>Rats, Inbred Lew</subject><subject>Receptor, Insulin - metabolism</subject><subject>Shc Signaling Adaptor Proteins</subject><subject>Signal Transduction</subject><subject>Src Homology 2 Domain-Containing, Transforming Protein 1</subject><subject>Streptozocin</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNptkm1rFDEQxxdRbK1-AkEWQUFwzzzubl6Ws7YHBwVbxXchm51sU_aSM8mq7ac3x50cJ8cEJjP85oHhXxSvMZoRSptPvVUdJIgzjmaYzEiDxJPiFAsqKkqaH0-LU4QwqXAjmpPiRYz3CKE62_PiBOOGUMTpafF4YQzoFEtvypsUYJ38o9fWlZ933Uvl-n1wG0ClFbhUdg_lIo6Qckq5uB6VSypZ78r8Fq78bn_57OM05l43dnAqf4YyB19VKq9AhfSyeGbUGOHVzp8V375c3M6vquX15WJ-vqw0b0WqGOc94QIE60RvoGm4UUpg2ivRauhxxw3joqadYaRmSDcMMK6F6XGPtVaYnhXvt33Xwf-cICa5slHDmFcGP0WZT4ERFiKDb_8D7_0U8uZRElwzgeqmzVC1hQY1grTO-BSUHsBBUKN3YGxOn2PG65ZwyjI_O8Jn62Fl9dGCDwcFmUnwJw1qilG2l8tDtjrGaj-OMIDMZ5xfH_J0y-vgYwxg5DrYlQoPEiO5EZX8JyrJkcREbkSVq97s7jJ1K-j3NTsVZeDdDlBRq9FkRWgb9xzDnLN2M_7jlruzw91vG2A_7tjcv-RX5Dg</recordid><startdate>20011201</startdate><enddate>20011201</enddate><creator>LAVIOLA, Luigi</creator><creator>BELSANTI, Gaetana</creator><creator>DAVALLI, Alberto M</creator><creator>NAPOLI, Raffaele</creator><creator>PERRINI, Sebastio</creator><creator>WEIR, Gordon C</creator><creator>GIORGINO, Riccardo</creator><creator>GIORGINO, Francesco</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>PHGZM</scope><scope>PHGZT</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQGLB</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>7X8</scope></search><sort><creationdate>20011201</creationdate><title>Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart</title><author>LAVIOLA, Luigi ; BELSANTI, Gaetana ; DAVALLI, Alberto M ; NAPOLI, Raffaele ; PERRINI, Sebastio ; WEIR, Gordon C ; GIORGINO, Riccardo ; GIORGINO, Francesco</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c589t-455d259e94b9dfe775faa913da98ced1b5f45963bf42640c74e1169fd1d1cca13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Adaptor Proteins, Signal Transducing</topic><topic>Adaptor Proteins, Vesicular Transport</topic><topic>Animals</topic><topic>Associated diseases and complications</topic><topic>Biological and medical sciences</topic><topic>Calcium-Calmodulin-Dependent Protein Kinases - metabolism</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Experimental - metabolism</topic><topic>Diabetes Mellitus, Experimental - surgery</topic><topic>Diabetes research</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Fatty acids</topic><topic>Glucose</topic><topic>Glycogen Synthase Kinase 3</topic><topic>Glycogen Synthase Kinases</topic><topic>Health aspects</topic><topic>Insulin</topic><topic>Insulin - metabolism</topic><topic>Insulin Receptor Substrate Proteins</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Islets of Langerhans Transplantation</topic><topic>Kinases</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mitogen-Activated Protein Kinase Kinases - metabolism</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Myocardium - metabolism</topic><topic>Oxidation</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>Phosphoproteins - metabolism</topic><topic>Phosphorylation</topic><topic>Phosphoserine - metabolism</topic><topic>Phosphotyrosine - metabolism</topic><topic>Protein-Serine-Threonine Kinases</topic><topic>Proteins</topic><topic>Proteins - metabolism</topic><topic>Proto-Oncogene Proteins - metabolism</topic><topic>Proto-Oncogene Proteins c-akt</topic><topic>Rats</topic><topic>Rats, Inbred Lew</topic><topic>Receptor, Insulin - metabolism</topic><topic>Shc Signaling Adaptor Proteins</topic><topic>Signal Transduction</topic><topic>Src Homology 2 Domain-Containing, Transforming Protein 1</topic><topic>Streptozocin</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>LAVIOLA, Luigi</creatorcontrib><creatorcontrib>BELSANTI, Gaetana</creatorcontrib><creatorcontrib>DAVALLI, Alberto M</creatorcontrib><creatorcontrib>NAPOLI, Raffaele</creatorcontrib><creatorcontrib>PERRINI, Sebastio</creatorcontrib><creatorcontrib>WEIR, Gordon C</creatorcontrib><creatorcontrib>GIORGINO, Riccardo</creatorcontrib><creatorcontrib>GIORGINO, Francesco</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 (ProQuest)</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 Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</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>LAVIOLA, Luigi</au><au>BELSANTI, Gaetana</au><au>DAVALLI, Alberto M</au><au>NAPOLI, Raffaele</au><au>PERRINI, Sebastio</au><au>WEIR, Gordon C</au><au>GIORGINO, Riccardo</au><au>GIORGINO, Francesco</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2001-12-01</date><risdate>2001</risdate><volume>50</volume><issue>12</issue><spage>2709</spage><epage>2720</epage><pages>2709-2720</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart
Luigi Laviola 1 ,
Gaetana Belsanti 1 ,
Alberto M. Davalli 2 ,
Raffaele Napoli 2 ,
Sebastio Perrini 1 ,
Gordon C. Weir 2 ,
Riccardo Giorgino 1 and
Francesco Giorgino 1
1 Internal Medicine, Endocrinology and Metabolic Diseases, Department of Emergency and Organ Transplantation, University of
Bari, Bari, Italy
2 Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
Abstract
The insulin signaling cascade was investigated in rat myocardium in vivo in the presence of streptozocin (STZ)-induced diabetes
and after diabetes treatment by islet transplantation under the kidney capsule. The levels of insulin-stimulated tyrosine
phosphorylation of the insulin receptor β-subunit, insulin receptor substrate (IRS)-2, and p52 Shc were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. The amount
of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2
were also elevated in diabetes, whereas no changes in IRS-1–associated PI 3-kinase were observed. Insulin-induced phosphorylation
of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. In contrast
with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate
of Akt, was markedly reduced in diabetes. In islet-transplanted rats, the majority of the alterations in insulin-signaling
proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association
with PI 3-kinase was blunted. In conclusion, in the diabetic heart, 1 ) IRS-1, IRS-2, and p52 Shc are differently altered, 2 ) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3 ) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3.
Islet transplantation under the kidney capsule is a potentially effective therapy to correct several diabetes-induced abnormalities
of insulin signaling in cardiac muscle but does not restore the responsiveness of all signaling reactions to insulin.
Footnotes
Address correspondence and reprint requests to Francesco Giorgino, MD, PhD, Internal Medicine, Endocrinology and Metabolic
Diseases, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare, 11, I-70124 Bari, Italy.
E-mail: giorginf{at}tin.it .
Received for publication 22 December 2000 and accepted in revised form 16 August 2001.
A.M.D. is currently affiliated with the Scientific Institute H San Raffaele, Milan, Italy.
R.N. is currently affiliated with the Department of Internal Medicine, University of Naples Federico II, Naples, Italy.
BSA, bovine serum albumin; Erk, extracellular signal-regulated kinase; GSK, glycogen synthase kinase; IRS, insulin receptor
substrate; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; PBS, phosphate-buffered saline; PDK, phosphoinositide-dependent
kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PP1, protein phosphatase 1; STZ, streptozocin.</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>11723053</pmid><doi>10.2337/diabetes.50.12.2709</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2001-12, Vol.50 (12), p.2709-2720 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_pascalfrancis_primary_14155484 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Adaptor Proteins, Signal Transducing Adaptor Proteins, Vesicular Transport Animals Associated diseases and complications Biological and medical sciences Calcium-Calmodulin-Dependent Protein Kinases - metabolism Diabetes Diabetes Mellitus, Experimental - metabolism Diabetes Mellitus, Experimental - surgery Diabetes research Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinopathies Fatty acids Glucose Glycogen Synthase Kinase 3 Glycogen Synthase Kinases Health aspects Insulin Insulin - metabolism Insulin Receptor Substrate Proteins Intracellular Signaling Peptides and Proteins Islets of Langerhans Transplantation Kinases Male Medical sciences Mitogen-Activated Protein Kinase Kinases - metabolism Mitogen-Activated Protein Kinases - metabolism Myocardium - metabolism Oxidation Phosphatidylinositol 3-Kinases - metabolism Phosphoproteins - metabolism Phosphorylation Phosphoserine - metabolism Phosphotyrosine - metabolism Protein-Serine-Threonine Kinases Proteins Proteins - metabolism Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-akt Rats Rats, Inbred Lew Receptor, Insulin - metabolism Shc Signaling Adaptor Proteins Signal Transduction Src Homology 2 Domain-Containing, Transforming Protein 1 Streptozocin |
| title | Effects of Streptozocin Diabetes and Diabetes Treatment by Islet Transplantation on In Vivo Insulin Signaling in Rat Heart |
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