A Pyruvate Cycling Pathway Involving Cytosolic NADP-dependent Isocitrate Dehydrogenase Regulates Glucose-stimulated Insulin Secretion
Glucose-stimulated insulin secretion (GSIS) from pancreatic islet β-cells is central to control of mammalian fuel homeostasis. Glucose metabolism mediates GSIS in part via ATP-regulated K+ (KATP) channels, but multiple lines of evidence suggest participation of other signals. Here we investigated th...
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| Veröffentlicht in: | The Journal of biological chemistry 2006-10, Vol.281 (41), p.30593-30602 |
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| container_title | The Journal of biological chemistry |
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| creator | Ronnebaum, Sarah M. Ilkayeva, Olga Burgess, Shawn C. Joseph, Jamie W. Lu, Danhong Stevens, Robert D. Becker, Thomas C. Sherry, A. Dean Newgard, Christopher B. Jensen, Mette V. |
| description | Glucose-stimulated insulin secretion (GSIS) from pancreatic islet β-cells is central to control of mammalian fuel homeostasis. Glucose metabolism mediates GSIS in part via ATP-regulated K+ (KATP) channels, but multiple lines of evidence suggest participation of other signals. Here we investigated the role of cytosolic NADP-dependent isocitrate dehydrogenase (ICDc) in control of GSIS in β-cells. Delivery of small interfering RNAs specific for ICDc caused impairment of GSIS in two independent robustly glucose-responsive rat insulinoma (INS-1-derived) cell lines and in primary rat islets. Suppression of ICDc also attenuated the glucose-induced increments in pyruvate cycling activity and in NADPH levels, a predicted by-product of pyruvate cycling pathways, as well as the total cellular NADP(H) content. Metabolic profiling of eight organic acids in cell extracts revealed that suppression of ICDc caused increases in lactate production in both INS-1-derived cell lines and primary islets, consistent with the attenuation of pyruvate cycling, with no significant changes in other intermediates. Based on these studies, we propose that a pyruvate cycling pathway involving ICDc plays an important role in control of GSIS. |
| doi_str_mv | 10.1074/jbc.M511908200 |
| format | Article |
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Suppression of ICDc also attenuated the glucose-induced increments in pyruvate cycling activity and in NADPH levels, a predicted by-product of pyruvate cycling pathways, as well as the total cellular NADP(H) content. Metabolic profiling of eight organic acids in cell extracts revealed that suppression of ICDc caused increases in lactate production in both INS-1-derived cell lines and primary islets, consistent with the attenuation of pyruvate cycling, with no significant changes in other intermediates. Based on these studies, we propose that a pyruvate cycling pathway involving ICDc plays an important role in control of GSIS.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M511908200</identifier><identifier>PMID: 16912049</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Cytosol - enzymology ; Glucose - metabolism ; Insulin - metabolism ; Insulin Secretion ; Islets of Langerhans - cytology ; Isocitrate Dehydrogenase - chemistry ; Lactates - metabolism ; Magnetic Resonance Spectroscopy ; Male ; Models, Biological ; Pyruvic Acid - chemistry ; Rats ; Rats, Sprague-Dawley</subject><ispartof>The Journal of biological chemistry, 2006-10, Vol.281 (41), p.30593-30602</ispartof><rights>2006 © 2006 ASBMB. 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Dean</creatorcontrib><creatorcontrib>Newgard, Christopher B.</creatorcontrib><creatorcontrib>Jensen, Mette V.</creatorcontrib><title>A Pyruvate Cycling Pathway Involving Cytosolic NADP-dependent Isocitrate Dehydrogenase Regulates Glucose-stimulated Insulin Secretion</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Glucose-stimulated insulin secretion (GSIS) from pancreatic islet β-cells is central to control of mammalian fuel homeostasis. Glucose metabolism mediates GSIS in part via ATP-regulated K+ (KATP) channels, but multiple lines of evidence suggest participation of other signals. Here we investigated the role of cytosolic NADP-dependent isocitrate dehydrogenase (ICDc) in control of GSIS in β-cells. Delivery of small interfering RNAs specific for ICDc caused impairment of GSIS in two independent robustly glucose-responsive rat insulinoma (INS-1-derived) cell lines and in primary rat islets. Suppression of ICDc also attenuated the glucose-induced increments in pyruvate cycling activity and in NADPH levels, a predicted by-product of pyruvate cycling pathways, as well as the total cellular NADP(H) content. Metabolic profiling of eight organic acids in cell extracts revealed that suppression of ICDc caused increases in lactate production in both INS-1-derived cell lines and primary islets, consistent with the attenuation of pyruvate cycling, with no significant changes in other intermediates. Based on these studies, we propose that a pyruvate cycling pathway involving ICDc plays an important role in control of GSIS.</description><subject>Animals</subject><subject>Cytosol - enzymology</subject><subject>Glucose - metabolism</subject><subject>Insulin - metabolism</subject><subject>Insulin Secretion</subject><subject>Islets of Langerhans - cytology</subject><subject>Isocitrate Dehydrogenase - chemistry</subject><subject>Lactates - metabolism</subject><subject>Magnetic Resonance Spectroscopy</subject><subject>Male</subject><subject>Models, Biological</subject><subject>Pyruvic Acid - chemistry</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kE9v1DAQxSMEokvhyhFyQNyyeOL8sY-rLZSVCqwolbhZjj1JXCXx1k62ygfge-MlK_WEL2O9-c2b0Yuit0DWQMrs032l1t9yAE5YSsizaAWE0YTm8Pt5tCIkhYSnObuIXnl_T8LLOLyMLqDgkIb_Kvqzifezm45yxHg7q84MTbyXY_so53g3HG13PCnbebTedkbF3zdX-0TjAQeNwxjvvFVmdKfpK2xn7WyDg_QY_8Rm6oLs4-tuUtZj4kfT_5N0MPZT2BTfonI4Gju8jl7UsvP45lwvo7svn39tvyY3P653281NonICY1KVKciioDnLaJVRKMqa15wpqIjWMnQ4rZguCC81VznNKwKsoByJLHSRViW9jD4uvgdnHyb0o-iNV9h1ckA7eVEwTkugLIDrBVTOeu-wFgdneulmAUScghchePEUfBh4d3aeqh71E35OOgAfFqA1TftoHIrKWNViL1IGIgNBSc5pwN4vWC2tkI0zXtzdpgQoASB5CadNbCEwBHU06IRXBgeFOpiqUWhr_nfkX05FqB4</recordid><startdate>20061013</startdate><enddate>20061013</enddate><creator>Ronnebaum, Sarah M.</creator><creator>Ilkayeva, Olga</creator><creator>Burgess, Shawn C.</creator><creator>Joseph, Jamie W.</creator><creator>Lu, Danhong</creator><creator>Stevens, Robert D.</creator><creator>Becker, Thomas C.</creator><creator>Sherry, A. Dean</creator><creator>Newgard, Christopher B.</creator><creator>Jensen, Mette V.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</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>7X8</scope></search><sort><creationdate>20061013</creationdate><title>A Pyruvate Cycling Pathway Involving Cytosolic NADP-dependent Isocitrate Dehydrogenase Regulates Glucose-stimulated Insulin Secretion</title><author>Ronnebaum, Sarah M. ; Ilkayeva, Olga ; Burgess, Shawn C. ; Joseph, Jamie W. ; Lu, Danhong ; Stevens, Robert D. ; Becker, Thomas C. ; Sherry, A. 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Dean</creatorcontrib><creatorcontrib>Newgard, Christopher B.</creatorcontrib><creatorcontrib>Jensen, Mette V.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ronnebaum, Sarah M.</au><au>Ilkayeva, Olga</au><au>Burgess, Shawn C.</au><au>Joseph, Jamie W.</au><au>Lu, Danhong</au><au>Stevens, Robert D.</au><au>Becker, Thomas C.</au><au>Sherry, A. Dean</au><au>Newgard, Christopher B.</au><au>Jensen, Mette V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Pyruvate Cycling Pathway Involving Cytosolic NADP-dependent Isocitrate Dehydrogenase Regulates Glucose-stimulated Insulin Secretion</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2006-10-13</date><risdate>2006</risdate><volume>281</volume><issue>41</issue><spage>30593</spage><epage>30602</epage><pages>30593-30602</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Glucose-stimulated insulin secretion (GSIS) from pancreatic islet β-cells is central to control of mammalian fuel homeostasis. Glucose metabolism mediates GSIS in part via ATP-regulated K+ (KATP) channels, but multiple lines of evidence suggest participation of other signals. Here we investigated the role of cytosolic NADP-dependent isocitrate dehydrogenase (ICDc) in control of GSIS in β-cells. Delivery of small interfering RNAs specific for ICDc caused impairment of GSIS in two independent robustly glucose-responsive rat insulinoma (INS-1-derived) cell lines and in primary rat islets. Suppression of ICDc also attenuated the glucose-induced increments in pyruvate cycling activity and in NADPH levels, a predicted by-product of pyruvate cycling pathways, as well as the total cellular NADP(H) content. Metabolic profiling of eight organic acids in cell extracts revealed that suppression of ICDc caused increases in lactate production in both INS-1-derived cell lines and primary islets, consistent with the attenuation of pyruvate cycling, with no significant changes in other intermediates. 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| subjects | Animals Cytosol - enzymology Glucose - metabolism Insulin - metabolism Insulin Secretion Islets of Langerhans - cytology Isocitrate Dehydrogenase - chemistry Lactates - metabolism Magnetic Resonance Spectroscopy Male Models, Biological Pyruvic Acid - chemistry Rats Rats, Sprague-Dawley |
| title | A Pyruvate Cycling Pathway Involving Cytosolic NADP-dependent Isocitrate Dehydrogenase Regulates Glucose-stimulated Insulin Secretion |
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