Inceptor counteracts insulin signalling in β-cells to control glycaemia
Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic β-cells causes overt diabetes in mice; thus, therapies that sensitize β-cells to insulin may protect patients with diabetes against β-cell failure 1 – 3 . Here we identify an inhibitor of insulin receptor (INSR) and IGF1 rec...
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| Veröffentlicht in: | Nature (London) 2021-02, Vol.590 (7845), p.326-331 |
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| creator | Ansarullah Jain, Chirag Far, Fataneh Fathi Homberg, Sarah Wißmiller, Katharina von Hahn, Felizitas Gräfin Raducanu, Aurelia Schirge, Silvia Sterr, Michael Bilekova, Sara Siehler, Johanna Wiener, Julius Oppenländer, Lena Morshedi, Amir Bastidas-Ponce, Aimée Collden, Gustav Irmler, Martin Beckers, Johannes Feuchtinger, Annette Grzybek, Michal Ahlbrecht, Christin Feederle, Regina Plettenburg, Oliver Müller, Timo D. Meier, Matthias Tschöp, Matthias H. Coskun, Ünal Lickert, Heiko |
| description | Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic β-cells causes overt diabetes in mice; thus, therapies that sensitize β-cells to insulin may protect patients with diabetes against β-cell failure
1
–
3
. Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse β-cells, which we name the insulin inhibitory receptor (inceptor; encoded by the gene
Iir
). Inceptor contains an extracellular cysteine-rich domain with similarities to INSR and IGF1R
4
, and a mannose 6-phosphate receptor domain that is also found in the IGF2 receptor (IGF2R)
5
. Knockout mice that lack inceptor (
Iir
−/−
) exhibit signs of hyperinsulinaemia and hypoglycaemia, and die within a few hours of birth. Molecular and cellular analyses of embryonic and postnatal pancreases from
Iir
−/−
mice showed an increase in the activation of INSR–IGF1R in
Iir
−/−
pancreatic tissue, resulting in an increase in the proliferation and mass of β-cells. Similarly, inducible β-cell-specific
Iir
−/−
knockout in adult mice and in ex vivo islets led to an increase in the activation of INSR–IGF1R and increased proliferation of β-cells, resulting in improved glucose tolerance in vivo. Mechanistically, inceptor interacts with INSR–IGF1R to facilitate clathrin-mediated endocytosis for receptor desensitization. Blocking this physical interaction using monoclonal antibodies against the extracellular domain of inceptor resulted in the retention of inceptor and INSR at the plasma membrane to sustain the activation of INSR–IGF1R in β-cells. Together, our findings show that inceptor shields insulin-producing β-cells from constitutive pathway activation, and identify inceptor as a potential molecular target for INSR–IGF1R sensitization and diabetes therapy.
The insulin inhibitory receptor (inceptor) is identified as a negative regulator of insulin and IGF1 signalling that could be targeted for β-cell regeneration in treatments for diabetes. |
| doi_str_mv | 10.1038/s41586-021-03225-8 |
| format | Article |
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1
–
3
. Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse β-cells, which we name the insulin inhibitory receptor (inceptor; encoded by the gene
Iir
). Inceptor contains an extracellular cysteine-rich domain with similarities to INSR and IGF1R
4
, and a mannose 6-phosphate receptor domain that is also found in the IGF2 receptor (IGF2R)
5
. Knockout mice that lack inceptor (
Iir
−/−
) exhibit signs of hyperinsulinaemia and hypoglycaemia, and die within a few hours of birth. Molecular and cellular analyses of embryonic and postnatal pancreases from
Iir
−/−
mice showed an increase in the activation of INSR–IGF1R in
Iir
−/−
pancreatic tissue, resulting in an increase in the proliferation and mass of β-cells. Similarly, inducible β-cell-specific
Iir
−/−
knockout in adult mice and in ex vivo islets led to an increase in the activation of INSR–IGF1R and increased proliferation of β-cells, resulting in improved glucose tolerance in vivo. Mechanistically, inceptor interacts with INSR–IGF1R to facilitate clathrin-mediated endocytosis for receptor desensitization. Blocking this physical interaction using monoclonal antibodies against the extracellular domain of inceptor resulted in the retention of inceptor and INSR at the plasma membrane to sustain the activation of INSR–IGF1R in β-cells. Together, our findings show that inceptor shields insulin-producing β-cells from constitutive pathway activation, and identify inceptor as a potential molecular target for INSR–IGF1R sensitization and diabetes therapy.
The insulin inhibitory receptor (inceptor) is identified as a negative regulator of insulin and IGF1 signalling that could be targeted for β-cell regeneration in treatments for diabetes.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/s41586-021-03225-8</identifier><identifier>PMID: 33505018</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/51 ; 14/19 ; 38/39 ; 38/61 ; 38/90 ; 42/34 ; 45/15 ; 631/443/319/1642/137 ; 631/80/86/2367 ; 64/60 ; Animals ; Beta cells ; Blood glucose ; Blood Glucose - analysis ; Blood Glucose - metabolism ; Cell activation ; Cell growth ; Cell Line ; Cell proliferation ; Cell Proliferation - drug effects ; Cell Size ; Clathrin ; Clathrin - metabolism ; Desensitization ; Diabetes ; Diabetes mellitus ; Domains ; Embryos ; Endocrine Cells - metabolism ; Endocytosis ; Endoplasmic Reticulum - metabolism ; Gene expression ; Glucose ; Glucose tolerance ; Glucose Tolerance Test ; Golgi Apparatus - metabolism ; Growth factors ; Homeostasis ; Humanities and Social Sciences ; Humans ; Hypoglycemia ; Immunological tolerance ; Insulin ; Insulin - metabolism ; Insulin Antagonists - metabolism ; Insulin resistance ; Insulin-Like Growth Factor I - metabolism ; Insulin-Secreting Cells - cytology ; Insulin-Secreting Cells - drug effects ; Insulin-Secreting Cells - metabolism ; Kinases ; Lysosomes - metabolism ; Male ; Mannose ; Membrane Proteins ; Metabolism ; Mice ; Monoclonal antibodies ; multidisciplinary ; Neoplasm Proteins - chemistry ; Neoplasm Proteins - metabolism ; Pancreas ; Principal components analysis ; Proteins ; Receptor, Insulin - metabolism ; Receptors ; Science ; Science (multidisciplinary) ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; Tamoxifen - pharmacology</subject><ispartof>Nature (London), 2021-02, Vol.590 (7845), p.326-331</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021. corrected publication 2021</rights><rights>Copyright Nature Publishing Group Feb 11, 2021</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-828b7954ab7ea2699cb76c2717d72840ecea033e9886055578458ad245771f9e3</citedby><cites>FETCH-LOGICAL-c375t-828b7954ab7ea2699cb76c2717d72840ecea033e9886055578458ad245771f9e3</cites><orcidid>0000-0002-0624-9339 ; 0000-0002-4744-371X ; 0000-0002-3981-367X ; 0000-0001-6699-1386 ; 0000-0002-4597-8825 ; 0000-0003-4375-3144 ; 0000-0003-3169-479X ; 0000-0002-0224-7563</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41586-021-03225-8$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41586-021-03225-8$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33505018$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ansarullah</creatorcontrib><creatorcontrib>Jain, Chirag</creatorcontrib><creatorcontrib>Far, Fataneh Fathi</creatorcontrib><creatorcontrib>Homberg, Sarah</creatorcontrib><creatorcontrib>Wißmiller, Katharina</creatorcontrib><creatorcontrib>von Hahn, Felizitas Gräfin</creatorcontrib><creatorcontrib>Raducanu, Aurelia</creatorcontrib><creatorcontrib>Schirge, Silvia</creatorcontrib><creatorcontrib>Sterr, Michael</creatorcontrib><creatorcontrib>Bilekova, Sara</creatorcontrib><creatorcontrib>Siehler, Johanna</creatorcontrib><creatorcontrib>Wiener, Julius</creatorcontrib><creatorcontrib>Oppenländer, Lena</creatorcontrib><creatorcontrib>Morshedi, Amir</creatorcontrib><creatorcontrib>Bastidas-Ponce, Aimée</creatorcontrib><creatorcontrib>Collden, Gustav</creatorcontrib><creatorcontrib>Irmler, Martin</creatorcontrib><creatorcontrib>Beckers, Johannes</creatorcontrib><creatorcontrib>Feuchtinger, Annette</creatorcontrib><creatorcontrib>Grzybek, Michal</creatorcontrib><creatorcontrib>Ahlbrecht, Christin</creatorcontrib><creatorcontrib>Feederle, Regina</creatorcontrib><creatorcontrib>Plettenburg, Oliver</creatorcontrib><creatorcontrib>Müller, Timo D.</creatorcontrib><creatorcontrib>Meier, Matthias</creatorcontrib><creatorcontrib>Tschöp, Matthias H.</creatorcontrib><creatorcontrib>Coskun, Ünal</creatorcontrib><creatorcontrib>Lickert, Heiko</creatorcontrib><title>Inceptor counteracts insulin signalling in β-cells to control glycaemia</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic β-cells causes overt diabetes in mice; thus, therapies that sensitize β-cells to insulin may protect patients with diabetes against β-cell failure
1
–
3
. Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse β-cells, which we name the insulin inhibitory receptor (inceptor; encoded by the gene
Iir
). Inceptor contains an extracellular cysteine-rich domain with similarities to INSR and IGF1R
4
, and a mannose 6-phosphate receptor domain that is also found in the IGF2 receptor (IGF2R)
5
. Knockout mice that lack inceptor (
Iir
−/−
) exhibit signs of hyperinsulinaemia and hypoglycaemia, and die within a few hours of birth. Molecular and cellular analyses of embryonic and postnatal pancreases from
Iir
−/−
mice showed an increase in the activation of INSR–IGF1R in
Iir
−/−
pancreatic tissue, resulting in an increase in the proliferation and mass of β-cells. Similarly, inducible β-cell-specific
Iir
−/−
knockout in adult mice and in ex vivo islets led to an increase in the activation of INSR–IGF1R and increased proliferation of β-cells, resulting in improved glucose tolerance in vivo. Mechanistically, inceptor interacts with INSR–IGF1R to facilitate clathrin-mediated endocytosis for receptor desensitization. Blocking this physical interaction using monoclonal antibodies against the extracellular domain of inceptor resulted in the retention of inceptor and INSR at the plasma membrane to sustain the activation of INSR–IGF1R in β-cells. Together, our findings show that inceptor shields insulin-producing β-cells from constitutive pathway activation, and identify inceptor as a potential molecular target for INSR–IGF1R sensitization and diabetes therapy.
The insulin inhibitory receptor (inceptor) is identified as a negative regulator of insulin and IGF1 signalling that could be targeted for β-cell regeneration in treatments for diabetes.</description><subject>13/1</subject><subject>13/51</subject><subject>14/19</subject><subject>38/39</subject><subject>38/61</subject><subject>38/90</subject><subject>42/34</subject><subject>45/15</subject><subject>631/443/319/1642/137</subject><subject>631/80/86/2367</subject><subject>64/60</subject><subject>Animals</subject><subject>Beta cells</subject><subject>Blood glucose</subject><subject>Blood Glucose - analysis</subject><subject>Blood Glucose - metabolism</subject><subject>Cell activation</subject><subject>Cell growth</subject><subject>Cell Line</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Size</subject><subject>Clathrin</subject><subject>Clathrin - metabolism</subject><subject>Desensitization</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Domains</subject><subject>Embryos</subject><subject>Endocrine Cells - metabolism</subject><subject>Endocytosis</subject><subject>Endoplasmic Reticulum - metabolism</subject><subject>Gene expression</subject><subject>Glucose</subject><subject>Glucose tolerance</subject><subject>Glucose Tolerance Test</subject><subject>Golgi Apparatus - metabolism</subject><subject>Growth factors</subject><subject>Homeostasis</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Hypoglycemia</subject><subject>Immunological tolerance</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin Antagonists - metabolism</subject><subject>Insulin resistance</subject><subject>Insulin-Like Growth Factor I - metabolism</subject><subject>Insulin-Secreting Cells - cytology</subject><subject>Insulin-Secreting Cells - drug effects</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Kinases</subject><subject>Lysosomes - metabolism</subject><subject>Male</subject><subject>Mannose</subject><subject>Membrane Proteins</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Monoclonal antibodies</subject><subject>multidisciplinary</subject><subject>Neoplasm Proteins - chemistry</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Pancreas</subject><subject>Principal components analysis</subject><subject>Proteins</subject><subject>Receptor, Insulin - metabolism</subject><subject>Receptors</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Tamoxifen - 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counteracts insulin signalling in β-cells to control glycaemia</title><author>Ansarullah ; Jain, Chirag ; Far, Fataneh Fathi ; Homberg, Sarah ; Wißmiller, Katharina ; von Hahn, Felizitas Gräfin ; Raducanu, Aurelia ; Schirge, Silvia ; Sterr, Michael ; Bilekova, Sara ; Siehler, Johanna ; Wiener, Julius ; Oppenländer, Lena ; Morshedi, Amir ; Bastidas-Ponce, Aimée ; Collden, Gustav ; Irmler, Martin ; Beckers, Johannes ; Feuchtinger, Annette ; Grzybek, Michal ; Ahlbrecht, Christin ; Feederle, Regina ; Plettenburg, Oliver ; Müller, Timo D. ; Meier, Matthias ; Tschöp, Matthias H. ; Coskun, Ünal ; Lickert, Heiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c375t-828b7954ab7ea2699cb76c2717d72840ecea033e9886055578458ad245771f9e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>13/1</topic><topic>13/51</topic><topic>14/19</topic><topic>38/39</topic><topic>38/61</topic><topic>38/90</topic><topic>42/34</topic><topic>45/15</topic><topic>631/443/319/1642/137</topic><topic>631/80/86/2367</topic><topic>64/60</topic><topic>Animals</topic><topic>Beta cells</topic><topic>Blood glucose</topic><topic>Blood Glucose - analysis</topic><topic>Blood Glucose - metabolism</topic><topic>Cell activation</topic><topic>Cell growth</topic><topic>Cell Line</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Size</topic><topic>Clathrin</topic><topic>Clathrin - metabolism</topic><topic>Desensitization</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Domains</topic><topic>Embryos</topic><topic>Endocrine Cells - metabolism</topic><topic>Endocytosis</topic><topic>Endoplasmic Reticulum - metabolism</topic><topic>Gene expression</topic><topic>Glucose</topic><topic>Glucose tolerance</topic><topic>Glucose Tolerance Test</topic><topic>Golgi Apparatus - metabolism</topic><topic>Growth factors</topic><topic>Homeostasis</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Hypoglycemia</topic><topic>Immunological tolerance</topic><topic>Insulin</topic><topic>Insulin - metabolism</topic><topic>Insulin Antagonists - metabolism</topic><topic>Insulin resistance</topic><topic>Insulin-Like Growth Factor I - metabolism</topic><topic>Insulin-Secreting Cells - cytology</topic><topic>Insulin-Secreting Cells - drug effects</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Kinases</topic><topic>Lysosomes - metabolism</topic><topic>Male</topic><topic>Mannose</topic><topic>Membrane Proteins</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Monoclonal antibodies</topic><topic>multidisciplinary</topic><topic>Neoplasm Proteins - chemistry</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Pancreas</topic><topic>Principal components analysis</topic><topic>Proteins</topic><topic>Receptor, Insulin - metabolism</topic><topic>Receptors</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Signaling</topic><topic>Tamoxifen - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ansarullah</creatorcontrib><creatorcontrib>Jain, Chirag</creatorcontrib><creatorcontrib>Far, Fataneh Fathi</creatorcontrib><creatorcontrib>Homberg, Sarah</creatorcontrib><creatorcontrib>Wißmiller, Katharina</creatorcontrib><creatorcontrib>von Hahn, Felizitas Gräfin</creatorcontrib><creatorcontrib>Raducanu, 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Martin</au><au>Beckers, Johannes</au><au>Feuchtinger, Annette</au><au>Grzybek, Michal</au><au>Ahlbrecht, Christin</au><au>Feederle, Regina</au><au>Plettenburg, Oliver</au><au>Müller, Timo D.</au><au>Meier, Matthias</au><au>Tschöp, Matthias H.</au><au>Coskun, Ünal</au><au>Lickert, Heiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inceptor counteracts insulin signalling in β-cells to control glycaemia</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2021-02-11</date><risdate>2021</risdate><volume>590</volume><issue>7845</issue><spage>326</spage><epage>331</epage><pages>326-331</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><abstract>Resistance to insulin and insulin-like growth factor 1 (IGF1) in pancreatic β-cells causes overt diabetes in mice; thus, therapies that sensitize β-cells to insulin may protect patients with diabetes against β-cell failure
1
–
3
. Here we identify an inhibitor of insulin receptor (INSR) and IGF1 receptor (IGF1R) signalling in mouse β-cells, which we name the insulin inhibitory receptor (inceptor; encoded by the gene
Iir
). Inceptor contains an extracellular cysteine-rich domain with similarities to INSR and IGF1R
4
, and a mannose 6-phosphate receptor domain that is also found in the IGF2 receptor (IGF2R)
5
. Knockout mice that lack inceptor (
Iir
−/−
) exhibit signs of hyperinsulinaemia and hypoglycaemia, and die within a few hours of birth. Molecular and cellular analyses of embryonic and postnatal pancreases from
Iir
−/−
mice showed an increase in the activation of INSR–IGF1R in
Iir
−/−
pancreatic tissue, resulting in an increase in the proliferation and mass of β-cells. Similarly, inducible β-cell-specific
Iir
−/−
knockout in adult mice and in ex vivo islets led to an increase in the activation of INSR–IGF1R and increased proliferation of β-cells, resulting in improved glucose tolerance in vivo. Mechanistically, inceptor interacts with INSR–IGF1R to facilitate clathrin-mediated endocytosis for receptor desensitization. Blocking this physical interaction using monoclonal antibodies against the extracellular domain of inceptor resulted in the retention of inceptor and INSR at the plasma membrane to sustain the activation of INSR–IGF1R in β-cells. Together, our findings show that inceptor shields insulin-producing β-cells from constitutive pathway activation, and identify inceptor as a potential molecular target for INSR–IGF1R sensitization and diabetes therapy.
The insulin inhibitory receptor (inceptor) is identified as a negative regulator of insulin and IGF1 signalling that could be targeted for β-cell regeneration in treatments for diabetes.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33505018</pmid><doi>10.1038/s41586-021-03225-8</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-0624-9339</orcidid><orcidid>https://orcid.org/0000-0002-4744-371X</orcidid><orcidid>https://orcid.org/0000-0002-3981-367X</orcidid><orcidid>https://orcid.org/0000-0001-6699-1386</orcidid><orcidid>https://orcid.org/0000-0002-4597-8825</orcidid><orcidid>https://orcid.org/0000-0003-4375-3144</orcidid><orcidid>https://orcid.org/0000-0003-3169-479X</orcidid><orcidid>https://orcid.org/0000-0002-0224-7563</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2021-02, Vol.590 (7845), p.326-331 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2482668622 |
| source | MEDLINE; Nature; SpringerLink Journals - AutoHoldings |
| subjects | 13/1 13/51 14/19 38/39 38/61 38/90 42/34 45/15 631/443/319/1642/137 631/80/86/2367 64/60 Animals Beta cells Blood glucose Blood Glucose - analysis Blood Glucose - metabolism Cell activation Cell growth Cell Line Cell proliferation Cell Proliferation - drug effects Cell Size Clathrin Clathrin - metabolism Desensitization Diabetes Diabetes mellitus Domains Embryos Endocrine Cells - metabolism Endocytosis Endoplasmic Reticulum - metabolism Gene expression Glucose Glucose tolerance Glucose Tolerance Test Golgi Apparatus - metabolism Growth factors Homeostasis Humanities and Social Sciences Humans Hypoglycemia Immunological tolerance Insulin Insulin - metabolism Insulin Antagonists - metabolism Insulin resistance Insulin-Like Growth Factor I - metabolism Insulin-Secreting Cells - cytology Insulin-Secreting Cells - drug effects Insulin-Secreting Cells - metabolism Kinases Lysosomes - metabolism Male Mannose Membrane Proteins Metabolism Mice Monoclonal antibodies multidisciplinary Neoplasm Proteins - chemistry Neoplasm Proteins - metabolism Pancreas Principal components analysis Proteins Receptor, Insulin - metabolism Receptors Science Science (multidisciplinary) Signal transduction Signal Transduction - drug effects Signaling Tamoxifen - pharmacology |
| title | Inceptor counteracts insulin signalling in β-cells to control glycaemia |
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