Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal
Weight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric b...
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| creator | Chen, Mimi Z Hudson, Claire A Vincent, Emma E de Berker, David A R May, Margaret T Hers, Ingeborg Dayan, Colin M Andrews, Robert C Tavaré, Jeremy M |
| description | Weight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric bypass surgery (RYGB), and compared this to lean volunteers.
The hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR) in eight morbidly obese (body mass index, BMI=47.3 ± 2.2 kg/m(2)) patients, before and after RYGB, and in eight lean volunteers (BMI=20.7 ± 0.7 kg/m2). Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50) and maximal (GDR100) GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity.
Pre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P |
| doi_str_mv | 10.1371/journal.pone.0120084 |
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The hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR) in eight morbidly obese (body mass index, BMI=47.3 ± 2.2 kg/m(2)) patients, before and after RYGB, and in eight lean volunteers (BMI=20.7 ± 0.7 kg/m2). Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50) and maximal (GDR100) GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity.
Pre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P<0.001). Weight-loss of 29.9 ± 4 kg after surgery significantly improved GDR50 (P=0.004) but not GDR100 (P=0.3). These subjects still remained significantly more insulin resistant than the lean individuals (p<0.001). Weight loss increased insulin-stimulated skeletal muscle Akt-Thr308 and Akt-Ser473 phosphorylation, P=0.02 and P=0.03 respectively (MANCOVA), and Akt activity towards the substrate PRAS40 (P=0.003, MANCOVA), and in contrast to GDR, were fully normalised after the surgery (obese vs lean, P=0.6, P=0.35, P=0.46, respectively).
Our data show that although Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal. This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0120084</identifier><identifier>PMID: 25876175</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adaptor Proteins, Signal Transducing - metabolism ; Adult ; AKT protein ; Bariatric Surgery ; Biomarkers ; Body mass ; Body mass index ; Body size ; Body weight loss ; Comparative analysis ; Female ; Gastric bypass ; Gastrointestinal surgery ; Glucose ; Glucose - metabolism ; Humans ; Insulin ; Insulin - metabolism ; Insulin Resistance ; Kinases ; Male ; Middle Aged ; Muscles ; Obesity ; Obesity, Morbid - metabolism ; Obesity, Morbid - surgery ; Phosphorylation ; Proto-Oncogene Proteins c-akt - metabolism ; Restoration ; Signal Transduction ; Signaling ; Skeletal muscle ; Substrates ; Surgery ; Weight loss ; Young Adult</subject><ispartof>PloS one, 2015-04, Vol.10 (4), p.e0120084-e0120084</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Chen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Chen et al 2015 Chen et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-d9d9fec9363281089c15947816d6913ff856b6533a74068c7377d95c9d63c2633</citedby><cites>FETCH-LOGICAL-c692t-d9d9fec9363281089c15947816d6913ff856b6533a74068c7377d95c9d63c2633</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/PMC4395354/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395354/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79343,79344</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25876175$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Mimi Z</creatorcontrib><creatorcontrib>Hudson, Claire A</creatorcontrib><creatorcontrib>Vincent, Emma E</creatorcontrib><creatorcontrib>de Berker, David A R</creatorcontrib><creatorcontrib>May, Margaret T</creatorcontrib><creatorcontrib>Hers, Ingeborg</creatorcontrib><creatorcontrib>Dayan, Colin M</creatorcontrib><creatorcontrib>Andrews, Robert C</creatorcontrib><creatorcontrib>Tavaré, Jeremy M</creatorcontrib><title>Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Weight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric bypass surgery (RYGB), and compared this to lean volunteers.
The hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR) in eight morbidly obese (body mass index, BMI=47.3 ± 2.2 kg/m(2)) patients, before and after RYGB, and in eight lean volunteers (BMI=20.7 ± 0.7 kg/m2). Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50) and maximal (GDR100) GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity.
Pre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P<0.001). Weight-loss of 29.9 ± 4 kg after surgery significantly improved GDR50 (P=0.004) but not GDR100 (P=0.3). These subjects still remained significantly more insulin resistant than the lean individuals (p<0.001). Weight loss increased insulin-stimulated skeletal muscle Akt-Thr308 and Akt-Ser473 phosphorylation, P=0.02 and P=0.03 respectively (MANCOVA), and Akt activity towards the substrate PRAS40 (P=0.003, MANCOVA), and in contrast to GDR, were fully normalised after the surgery (obese vs lean, P=0.6, P=0.35, P=0.46, respectively).
Our data show that although Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal. This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss.</description><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Adult</subject><subject>AKT protein</subject><subject>Bariatric Surgery</subject><subject>Biomarkers</subject><subject>Body mass</subject><subject>Body mass index</subject><subject>Body size</subject><subject>Body weight loss</subject><subject>Comparative analysis</subject><subject>Female</subject><subject>Gastric bypass</subject><subject>Gastrointestinal surgery</subject><subject>Glucose</subject><subject>Glucose - metabolism</subject><subject>Humans</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin Resistance</subject><subject>Kinases</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Muscles</subject><subject>Obesity</subject><subject>Obesity, Morbid - metabolism</subject><subject>Obesity, Morbid - surgery</subject><subject>Phosphorylation</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Restoration</subject><subject>Signal Transduction</subject><subject>Signaling</subject><subject>Skeletal muscle</subject><subject>Substrates</subject><subject>Surgery</subject><subject>Weight loss</subject><subject>Young Adult</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk12P1CAUhhujcdfVf2C0iYnRixmhUFpuTNaNH5Nssolft4QC7TChZZZDjfMH_N0yOx-Zmr0wXEAOz3kPvHCy7DlGc0wq_G7lxzBIN1_7wcwRLhCq6YPsHHNSzFiByMOT9Vn2BGCFUElqxh5nZ0VZVwxX5Xn254MMVsZgVQ5j6EzY5HbIex8aq90m940BkyIwuhQOBixEOcR8OfZygHzwoZfOgoEjA7ZLp0qrLm_GmIh42JpBtP3oZDQ679yofFLWFtYepHuaPWqlA_NsP19kPz59_H71ZXZ983lxdXk9U4wXcaa55q1RnDBS1BjVXOGS06rGTDOOSdvWJWtYSYisKGK1qkhVaV4qrhlRBSPkInu50107D2JvIQjMKpIcLHCRiMWO0F6uxDrYXoaN8NKKu4APnZAhWuWMqChtNFGmbqihFHFeK01YK0tNS11wlLTe76uNTW-0MkMM0k1EpzuDXYrO_xKU8JKUNAm82QsEfzsaiKK3oIxzcjB-vDs3TcZQvK316h_0_tvtqU6mC9ih9amu2oqKS1okhlFUJWp-D5WGNr1V6b-1NsUnCW8nCYmJ5nfs5AggFt--_j9783PKvj5hl0a6uATvxmj9AFOQ7kAVPEAw7dFkjMS2XQ5uiG27iH27pLQXpw90TDr0B_kLHlsRhw</recordid><startdate>20150413</startdate><enddate>20150413</enddate><creator>Chen, Mimi Z</creator><creator>Hudson, Claire A</creator><creator>Vincent, Emma E</creator><creator>de Berker, David A R</creator><creator>May, Margaret T</creator><creator>Hers, Ingeborg</creator><creator>Dayan, Colin M</creator><creator>Andrews, Robert C</creator><creator>Tavaré, Jeremy M</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150413</creationdate><title>Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal</title><author>Chen, Mimi Z ; Hudson, Claire A ; Vincent, Emma E ; de Berker, David A R ; May, Margaret T ; Hers, Ingeborg ; Dayan, Colin M ; Andrews, Robert C ; Tavaré, Jeremy M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-d9d9fec9363281089c15947816d6913ff856b6533a74068c7377d95c9d63c2633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Adult</topic><topic>AKT protein</topic><topic>Bariatric Surgery</topic><topic>Biomarkers</topic><topic>Body mass</topic><topic>Body mass index</topic><topic>Body size</topic><topic>Body weight loss</topic><topic>Comparative analysis</topic><topic>Female</topic><topic>Gastric bypass</topic><topic>Gastrointestinal surgery</topic><topic>Glucose</topic><topic>Glucose - metabolism</topic><topic>Humans</topic><topic>Insulin</topic><topic>Insulin - metabolism</topic><topic>Insulin Resistance</topic><topic>Kinases</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Muscles</topic><topic>Obesity</topic><topic>Obesity, Morbid - metabolism</topic><topic>Obesity, Morbid - surgery</topic><topic>Phosphorylation</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Restoration</topic><topic>Signal Transduction</topic><topic>Signaling</topic><topic>Skeletal muscle</topic><topic>Substrates</topic><topic>Surgery</topic><topic>Weight loss</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Mimi Z</creatorcontrib><creatorcontrib>Hudson, Claire A</creatorcontrib><creatorcontrib>Vincent, Emma E</creatorcontrib><creatorcontrib>de Berker, David A R</creatorcontrib><creatorcontrib>May, Margaret T</creatorcontrib><creatorcontrib>Hers, Ingeborg</creatorcontrib><creatorcontrib>Dayan, Colin M</creatorcontrib><creatorcontrib>Andrews, Robert C</creatorcontrib><creatorcontrib>Tavaré, Jeremy M</creatorcontrib><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: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database (ProQuest)</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>ProQuest - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Mimi Z</au><au>Hudson, Claire A</au><au>Vincent, Emma E</au><au>de Berker, David A R</au><au>May, Margaret T</au><au>Hers, Ingeborg</au><au>Dayan, Colin M</au><au>Andrews, Robert C</au><au>Tavaré, Jeremy M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-04-13</date><risdate>2015</risdate><volume>10</volume><issue>4</issue><spage>e0120084</spage><epage>e0120084</epage><pages>e0120084-e0120084</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Weight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric bypass surgery (RYGB), and compared this to lean volunteers.
The hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR) in eight morbidly obese (body mass index, BMI=47.3 ± 2.2 kg/m(2)) patients, before and after RYGB, and in eight lean volunteers (BMI=20.7 ± 0.7 kg/m2). Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50) and maximal (GDR100) GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity.
Pre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P<0.001). Weight-loss of 29.9 ± 4 kg after surgery significantly improved GDR50 (P=0.004) but not GDR100 (P=0.3). These subjects still remained significantly more insulin resistant than the lean individuals (p<0.001). Weight loss increased insulin-stimulated skeletal muscle Akt-Thr308 and Akt-Ser473 phosphorylation, P=0.02 and P=0.03 respectively (MANCOVA), and Akt activity towards the substrate PRAS40 (P=0.003, MANCOVA), and in contrast to GDR, were fully normalised after the surgery (obese vs lean, P=0.6, P=0.35, P=0.46, respectively).
Our data show that although Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal. This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25876175</pmid><doi>10.1371/journal.pone.0120084</doi><oa>free_for_read</oa></addata></record> |
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| issn | 1932-6203 1932-6203 |
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| subjects | Adaptor Proteins, Signal Transducing - metabolism Adult AKT protein Bariatric Surgery Biomarkers Body mass Body mass index Body size Body weight loss Comparative analysis Female Gastric bypass Gastrointestinal surgery Glucose Glucose - metabolism Humans Insulin Insulin - metabolism Insulin Resistance Kinases Male Middle Aged Muscles Obesity Obesity, Morbid - metabolism Obesity, Morbid - surgery Phosphorylation Proto-Oncogene Proteins c-akt - metabolism Restoration Signal Transduction Signaling Skeletal muscle Substrates Surgery Weight loss Young Adult |
| title | Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T08%3A47%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Bariatric%20surgery%20in%20morbidly%20obese%20insulin%20resistant%20humans%20normalises%20insulin%20signalling%20but%20not%20insulin-stimulated%20glucose%20disposal&rft.jtitle=PloS%20one&rft.au=Chen,%20Mimi%20Z&rft.date=2015-04-13&rft.volume=10&rft.issue=4&rft.spage=e0120084&rft.epage=e0120084&rft.pages=e0120084-e0120084&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0120084&rft_dat=%3Cgale_plos_%3EA422026407%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1673120212&rft_id=info:pmid/25876175&rft_galeid=A422026407&rft_doaj_id=oai_doaj_org_article_744bd3ce8b4e440998cd36fa5d45d290&rfr_iscdi=true |