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Adaptive changes of human islets to an obesogenic environment in the mouse
Aims/hypothesis In this study, we used an immunodeficient mouse model to explore, in vivo, the longitudinal adaptation of human islets to an obesogenic environment. Methods Non-diabetic Rag2 –/– mice ( n = 61) were transplanted with human islets (400 islet equivalents [IEQ]) from six pancreases: fo...
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| Published in: | Diabetologia 2013-02, Vol.56 (2), p.350-358 |
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| creator | Gargani, S. Thévenet, J. Yuan, J. E. Lefebvre, B. Delalleau, N. Gmyr, V. Hubert, T. Duhamel, A. Pattou, F. Kerr-Conte, J. |
| description | Aims/hypothesis
In this study, we used an immunodeficient mouse model to explore, in vivo, the longitudinal adaptation of human islets to an obesogenic environment.
Methods
Non-diabetic
Rag2
–/–
mice (
n
= 61) were transplanted with human islets (400 islet equivalents [IEQ]) from six pancreases: four non-diabetic and two with overt metabolic dysfunction (older, high HbA
lc
or history of diabetes). Animals were fed for 12 weeks with a control or high-fat diet (HFD), and followed for weight, serum triacylglycerol, fasting blood glucose and human C-peptide. After the mice were killed, human grafts and the endogenous pancreas were analysed for endocrine volume, distribution of beta and alpha cells, and proliferation.
Results
Transplanted mice on an HFD gained significantly more weight (
p
|
| doi_str_mv | 10.1007/s00125-012-2775-y |
| format | article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3536990</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3192965871</sourcerecordid><originalsourceid>FETCH-LOGICAL-c500t-6ac24b5bd553e736d94d50131388eddfe0f596ced9aa3964fe062afce6ec3cb33</originalsourceid><addsrcrecordid>eNp1kU1r3DAQhkVpabZJf0AvRVAKvbgdSZa8ugRC6EdKoJcWehOyPN5VsKWNZC_sv4-W3aRJoJcR0jzzzoxeQt4x-MwAmi8ZgHFZlVDxppHV7gVZsFrwCmq-fEkW-3TFlurvCXmT8w0ACFmr1-SEC6a50mJBfl50djP5LVK3tmGFmcaerufRBurzgFOmU6TlElvMcYXBO4ph61MMI4aJ-kCnNdIxzhnPyKveDhnfHs9T8ufb19-XP6rrX9-vLi-uKycBpkpZx-tWtp2UAhuhOl13EphgYrnErusReqmVw05bK7Sqy4Pitneo0AnXCnFKzg-6m7kdsXNljmQHs0l-tGlnovXmaSb4tVnFrRFSKK2hCHw6CqR4O2OezOizw2GwAcsihvFGcKYYNAX98Ay9iXMKZT3Das0ZCGCsUOxAuRRzTtg_DMPA7J0yB6dMCWbvlNmVmvePt3iouLemAB-PgM3ODn2ywfn8j2tk-TK15_iByyVVHEyPRvxv9zv_wqzk</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1492103011</pqid></control><display><type>article</type><title>Adaptive changes of human islets to an obesogenic environment in the mouse</title><source>Springer Nature:Jisc Collections:Springer Nature Read and Publish 2023-2025: Springer Reading List</source><creator>Gargani, S. ; Thévenet, J. ; Yuan, J. E. ; Lefebvre, B. ; Delalleau, N. ; Gmyr, V. ; Hubert, T. ; Duhamel, A. ; Pattou, F. ; Kerr-Conte, J.</creator><creatorcontrib>Gargani, S. ; Thévenet, J. ; Yuan, J. E. ; Lefebvre, B. ; Delalleau, N. ; Gmyr, V. ; Hubert, T. ; Duhamel, A. ; Pattou, F. ; Kerr-Conte, J.</creatorcontrib><description>Aims/hypothesis
In this study, we used an immunodeficient mouse model to explore, in vivo, the longitudinal adaptation of human islets to an obesogenic environment.
Methods
Non-diabetic
Rag2
–/–
mice (
n
= 61) were transplanted with human islets (400 islet equivalents [IEQ]) from six pancreases: four non-diabetic and two with overt metabolic dysfunction (older, high HbA
lc
or history of diabetes). Animals were fed for 12 weeks with a control or high-fat diet (HFD), and followed for weight, serum triacylglycerol, fasting blood glucose and human C-peptide. After the mice were killed, human grafts and the endogenous pancreas were analysed for endocrine volume, distribution of beta and alpha cells, and proliferation.
Results
Transplanted mice on an HFD gained significantly more weight (
p
< 0.001) and had higher fasting glycaemia (2–12 weeks;
p
= 0.0002) and consistently higher fasting human C-peptide levels (2–12 weeks;
p
= 0.04) compared with those on the control diet. Histology demonstrated doubling of human islet graft volume at 12 weeks in animals on the HFD and increased beta cell volume (
p
< 0.001), but no change in alpha cell volume. Human islet function (hyperbolic product HOMA2%BS) at 12 weeks was four times lower in HFD animals (
p
< 0.001 vs controls) because of insufficient beta cell adaptation to decreased (70%) sensitivity (HOMA%S). Human islets obtained from donors with metabolic dysfunction failed to adapt to the HFD.
Conclusions/interpretation
This longitudinal study provides direct evidence that human islets adapt both endocrine and beta cell mass, function and gene expression to obesity in vivo. The present model will facilitate the identification of mechanisms by which human islets adapt to obesity in vivo and the cell type(s) responsible, and factors predisposing human beta cells to decompensation.</description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/s00125-012-2775-y</identifier><identifier>PMID: 23192693</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Adaptation ; Animals ; Biological and medical sciences ; Diabetes ; Diabetes. Impaired glucose tolerance ; Diet ; Diet, High-Fat - adverse effects ; DNA-Binding Proteins - deficiency ; DNA-Binding Proteins - genetics ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Gene expression ; Glucose ; Histology ; Human Physiology ; Humans ; Immunohistochemistry ; Insulin resistance ; Insulin-Secreting Cells - metabolism ; Internal Medicine ; Islets of Langerhans - metabolism ; Islets of Langerhans - physiology ; Islets of Langerhans Transplantation ; Longitudinal studies ; Male ; Medical sciences ; Medicine ; Medicine & Public Health ; Metabolic Diseases ; Metabolism ; Mice ; Obesity ; Obesity - metabolism ; Peptides ; Polymerase Chain Reaction</subject><ispartof>Diabetologia, 2013-02, Vol.56 (2), p.350-358</ispartof><rights>The Author(s) 2012</rights><rights>2014 INIST-CNRS</rights><rights>Springer-Verlag Berlin Heidelberg 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c500t-6ac24b5bd553e736d94d50131388eddfe0f596ced9aa3964fe062afce6ec3cb33</citedby><cites>FETCH-LOGICAL-c500t-6ac24b5bd553e736d94d50131388eddfe0f596ced9aa3964fe062afce6ec3cb33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27531363$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23192693$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gargani, S.</creatorcontrib><creatorcontrib>Thévenet, J.</creatorcontrib><creatorcontrib>Yuan, J. E.</creatorcontrib><creatorcontrib>Lefebvre, B.</creatorcontrib><creatorcontrib>Delalleau, N.</creatorcontrib><creatorcontrib>Gmyr, V.</creatorcontrib><creatorcontrib>Hubert, T.</creatorcontrib><creatorcontrib>Duhamel, A.</creatorcontrib><creatorcontrib>Pattou, F.</creatorcontrib><creatorcontrib>Kerr-Conte, J.</creatorcontrib><title>Adaptive changes of human islets to an obesogenic environment in the mouse</title><title>Diabetologia</title><addtitle>Diabetologia</addtitle><addtitle>Diabetologia</addtitle><description>Aims/hypothesis
In this study, we used an immunodeficient mouse model to explore, in vivo, the longitudinal adaptation of human islets to an obesogenic environment.
Methods
Non-diabetic
Rag2
–/–
mice (
n
= 61) were transplanted with human islets (400 islet equivalents [IEQ]) from six pancreases: four non-diabetic and two with overt metabolic dysfunction (older, high HbA
lc
or history of diabetes). Animals were fed for 12 weeks with a control or high-fat diet (HFD), and followed for weight, serum triacylglycerol, fasting blood glucose and human C-peptide. After the mice were killed, human grafts and the endogenous pancreas were analysed for endocrine volume, distribution of beta and alpha cells, and proliferation.
Results
Transplanted mice on an HFD gained significantly more weight (
p
< 0.001) and had higher fasting glycaemia (2–12 weeks;
p
= 0.0002) and consistently higher fasting human C-peptide levels (2–12 weeks;
p
= 0.04) compared with those on the control diet. Histology demonstrated doubling of human islet graft volume at 12 weeks in animals on the HFD and increased beta cell volume (
p
< 0.001), but no change in alpha cell volume. Human islet function (hyperbolic product HOMA2%BS) at 12 weeks was four times lower in HFD animals (
p
< 0.001 vs controls) because of insufficient beta cell adaptation to decreased (70%) sensitivity (HOMA%S). Human islets obtained from donors with metabolic dysfunction failed to adapt to the HFD.
Conclusions/interpretation
This longitudinal study provides direct evidence that human islets adapt both endocrine and beta cell mass, function and gene expression to obesity in vivo. The present model will facilitate the identification of mechanisms by which human islets adapt to obesity in vivo and the cell type(s) responsible, and factors predisposing human beta cells to decompensation.</description><subject>Adaptation</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Diabetes</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Diet</subject><subject>Diet, High-Fat - adverse effects</subject><subject>DNA-Binding Proteins - deficiency</subject><subject>DNA-Binding Proteins - genetics</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Gene expression</subject><subject>Glucose</subject><subject>Histology</subject><subject>Human Physiology</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Insulin resistance</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Internal Medicine</subject><subject>Islets of Langerhans - metabolism</subject><subject>Islets of Langerhans - physiology</subject><subject>Islets of Langerhans Transplantation</subject><subject>Longitudinal studies</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metabolic Diseases</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Obesity</subject><subject>Obesity - metabolism</subject><subject>Peptides</subject><subject>Polymerase Chain Reaction</subject><issn>0012-186X</issn><issn>1432-0428</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNp1kU1r3DAQhkVpabZJf0AvRVAKvbgdSZa8ugRC6EdKoJcWehOyPN5VsKWNZC_sv4-W3aRJoJcR0jzzzoxeQt4x-MwAmi8ZgHFZlVDxppHV7gVZsFrwCmq-fEkW-3TFlurvCXmT8w0ACFmr1-SEC6a50mJBfl50djP5LVK3tmGFmcaerufRBurzgFOmU6TlElvMcYXBO4ph61MMI4aJ-kCnNdIxzhnPyKveDhnfHs9T8ufb19-XP6rrX9-vLi-uKycBpkpZx-tWtp2UAhuhOl13EphgYrnErusReqmVw05bK7Sqy4Pitneo0AnXCnFKzg-6m7kdsXNljmQHs0l-tGlnovXmaSb4tVnFrRFSKK2hCHw6CqR4O2OezOizw2GwAcsihvFGcKYYNAX98Ay9iXMKZT3Das0ZCGCsUOxAuRRzTtg_DMPA7J0yB6dMCWbvlNmVmvePt3iouLemAB-PgM3ODn2ywfn8j2tk-TK15_iByyVVHEyPRvxv9zv_wqzk</recordid><startdate>20130201</startdate><enddate>20130201</enddate><creator>Gargani, S.</creator><creator>Thévenet, J.</creator><creator>Yuan, J. E.</creator><creator>Lefebvre, B.</creator><creator>Delalleau, N.</creator><creator>Gmyr, V.</creator><creator>Hubert, T.</creator><creator>Duhamel, A.</creator><creator>Pattou, F.</creator><creator>Kerr-Conte, J.</creator><general>Springer-Verlag</general><general>Springer</general><general>Springer Nature B.V</general><scope>C6C</scope><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>3V.</scope><scope>7T5</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130201</creationdate><title>Adaptive changes of human islets to an obesogenic environment in the mouse</title><author>Gargani, S. ; Thévenet, J. ; Yuan, J. E. ; Lefebvre, B. ; Delalleau, N. ; Gmyr, V. ; Hubert, T. ; Duhamel, A. ; Pattou, F. ; Kerr-Conte, J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c500t-6ac24b5bd553e736d94d50131388eddfe0f596ced9aa3964fe062afce6ec3cb33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adaptation</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Diabetes</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Diet</topic><topic>Diet, High-Fat - adverse effects</topic><topic>DNA-Binding Proteins - deficiency</topic><topic>DNA-Binding Proteins - genetics</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Gene expression</topic><topic>Glucose</topic><topic>Histology</topic><topic>Human Physiology</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Insulin resistance</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Internal Medicine</topic><topic>Islets of Langerhans - metabolism</topic><topic>Islets of Langerhans - physiology</topic><topic>Islets of Langerhans Transplantation</topic><topic>Longitudinal studies</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metabolic Diseases</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Obesity</topic><topic>Obesity - metabolism</topic><topic>Peptides</topic><topic>Polymerase Chain Reaction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gargani, S.</creatorcontrib><creatorcontrib>Thévenet, J.</creatorcontrib><creatorcontrib>Yuan, J. E.</creatorcontrib><creatorcontrib>Lefebvre, B.</creatorcontrib><creatorcontrib>Delalleau, N.</creatorcontrib><creatorcontrib>Gmyr, V.</creatorcontrib><creatorcontrib>Hubert, T.</creatorcontrib><creatorcontrib>Duhamel, A.</creatorcontrib><creatorcontrib>Pattou, F.</creatorcontrib><creatorcontrib>Kerr-Conte, J.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><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>ProQuest Central (Corporate)</collection><collection>Immunology Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetologia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gargani, S.</au><au>Thévenet, J.</au><au>Yuan, J. E.</au><au>Lefebvre, B.</au><au>Delalleau, N.</au><au>Gmyr, V.</au><au>Hubert, T.</au><au>Duhamel, A.</au><au>Pattou, F.</au><au>Kerr-Conte, J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adaptive changes of human islets to an obesogenic environment in the mouse</atitle><jtitle>Diabetologia</jtitle><stitle>Diabetologia</stitle><addtitle>Diabetologia</addtitle><date>2013-02-01</date><risdate>2013</risdate><volume>56</volume><issue>2</issue><spage>350</spage><epage>358</epage><pages>350-358</pages><issn>0012-186X</issn><eissn>1432-0428</eissn><abstract>Aims/hypothesis
In this study, we used an immunodeficient mouse model to explore, in vivo, the longitudinal adaptation of human islets to an obesogenic environment.
Methods
Non-diabetic
Rag2
–/–
mice (
n
= 61) were transplanted with human islets (400 islet equivalents [IEQ]) from six pancreases: four non-diabetic and two with overt metabolic dysfunction (older, high HbA
lc
or history of diabetes). Animals were fed for 12 weeks with a control or high-fat diet (HFD), and followed for weight, serum triacylglycerol, fasting blood glucose and human C-peptide. After the mice were killed, human grafts and the endogenous pancreas were analysed for endocrine volume, distribution of beta and alpha cells, and proliferation.
Results
Transplanted mice on an HFD gained significantly more weight (
p
< 0.001) and had higher fasting glycaemia (2–12 weeks;
p
= 0.0002) and consistently higher fasting human C-peptide levels (2–12 weeks;
p
= 0.04) compared with those on the control diet. Histology demonstrated doubling of human islet graft volume at 12 weeks in animals on the HFD and increased beta cell volume (
p
< 0.001), but no change in alpha cell volume. Human islet function (hyperbolic product HOMA2%BS) at 12 weeks was four times lower in HFD animals (
p
< 0.001 vs controls) because of insufficient beta cell adaptation to decreased (70%) sensitivity (HOMA%S). Human islets obtained from donors with metabolic dysfunction failed to adapt to the HFD.
Conclusions/interpretation
This longitudinal study provides direct evidence that human islets adapt both endocrine and beta cell mass, function and gene expression to obesity in vivo. The present model will facilitate the identification of mechanisms by which human islets adapt to obesity in vivo and the cell type(s) responsible, and factors predisposing human beta cells to decompensation.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>23192693</pmid><doi>10.1007/s00125-012-2775-y</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Diabetologia, 2013-02, Vol.56 (2), p.350-358 |
| issn | 0012-186X 1432-0428 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3536990 |
| source | Springer Nature:Jisc Collections:Springer Nature Read and Publish 2023-2025: Springer Reading List |
| subjects | Adaptation Animals Biological and medical sciences Diabetes Diabetes. Impaired glucose tolerance Diet Diet, High-Fat - adverse effects DNA-Binding Proteins - deficiency DNA-Binding Proteins - genetics Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Gene expression Glucose Histology Human Physiology Humans Immunohistochemistry Insulin resistance Insulin-Secreting Cells - metabolism Internal Medicine Islets of Langerhans - metabolism Islets of Langerhans - physiology Islets of Langerhans Transplantation Longitudinal studies Male Medical sciences Medicine Medicine & Public Health Metabolic Diseases Metabolism Mice Obesity Obesity - metabolism Peptides Polymerase Chain Reaction |
| title | Adaptive changes of human islets to an obesogenic environment in the mouse |
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