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dc.contributor.authorSkovsø, Søs
dc.contributor.authorPanzhinskiy, Evgeniy
dc.contributor.authorKolic, Jelena
dc.contributor.authorCen, Haoning Howard
dc.contributor.authorDionne, Derek A
dc.contributor.authorDai, Xiao-Qing
dc.contributor.authorSharma, Rohit B
dc.contributor.authorElghazi, Lynda
dc.contributor.authorEllis, Cara E
dc.contributor.authorFaulkner, Katharine
dc.contributor.authorMarcil, Stephanie A M
dc.contributor.authorOverby, Peter
dc.contributor.authorNoursadeghi, Nilou
dc.contributor.authorHutchinson, Daria
dc.contributor.authorHu, Xiaoke
dc.contributor.authorLi, Hong
dc.contributor.authorModi, Honey
dc.contributor.authorWildi, Jennifer S
dc.contributor.authorBotezelli, J Diego
dc.contributor.authorNoh, Hye Lim
dc.contributor.authorSuk, Sujin
dc.contributor.authorGablaski, Brian
dc.contributor.authorBautista, Austin
dc.contributor.authorKim, Ryekjang
dc.contributor.authorCras-Méneur, Corentin
dc.contributor.authorFlibotte, Stephane
dc.contributor.authorSinha, Sunita
dc.contributor.authorLuciani, Dan S
dc.contributor.authorNislow, Corey
dc.contributor.authorRideout, Elizabeth J
dc.contributor.authorCytrynbaum, Eric N
dc.contributor.authorKim, Jason K
dc.contributor.authorBernal-Mizrachi, Ernesto
dc.contributor.authorAlonso, Laura C
dc.contributor.authorMacDonald, Patrick E
dc.contributor.authorJohnson, James D
dc.date.accessioned2023-07-19T19:18:29Z
dc.date.available2023-07-19T19:18:29Z
dc.date.issued2022-02-08
dc.identifier.citationSkovsø S, Panzhinskiy E, Kolic J, Cen HH, Dionne DA, Dai XQ, Sharma RB, Elghazi L, Ellis CE, Faulkner K, Marcil SAM, Overby P, Noursadeghi N, Hutchinson D, Hu X, Li H, Modi H, Wildi JS, Botezelli JD, Noh HL, Suk S, Gablaski B, Bautista A, Kim R, Cras-Méneur C, Flibotte S, Sinha S, Luciani DS, Nislow C, Rideout EJ, Cytrynbaum EN, Kim JK, Bernal-Mizrachi E, Alonso LC, MacDonald PE, Johnson JD. Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance. Nat Commun. 2022 Feb 8;13(1):735. doi: 10.1038/s41467-022-28039-8. PMID: 35136059; PMCID: PMC8826929.en_US
dc.identifier.eissn2041-1723
dc.identifier.doi10.1038/s41467-022-28039-8en_US
dc.identifier.pmid35136059
dc.identifier.urihttp://hdl.handle.net/20.500.14038/52312
dc.description.abstractInsulin receptor (Insr) protein is present at higher levels in pancreatic β-cells than in most other tissues, but the consequences of β-cell insulin resistance remain enigmatic. Here, we use an Ins1cre knock-in allele to delete Insr specifically in β-cells of both female and male mice. We compare experimental mice to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of purified recombined β-cells reveals transcriptomic consequences of Insr loss, which differ between female and male mice. Action potential and calcium oscillation frequencies are increased in Insr knockout β-cells from female, but not male mice, whereas only male βInsrKO islets have reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. Female βInsrKO and βInsrHET mice exhibit elevated insulin release in ex vivo perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr does not alter β-cell area up to 9 months of age, nor does it impair hyperglycemia-induced proliferation. Based on our data, we adapt a mathematical model to include β-cell insulin resistance, which predicts that β-cell Insr knockout improves glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance is significantly improved in female βInsrKO and βInsrHET mice compared to controls at 9, 21 and 39 weeks, and also in insulin-sensitive 4-week old males. We observe no improved glucose tolerance in older male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of β-cell specific insulin resistance. The propensity for hyperinsulinemia is associated with mildly reduced fasting glucose and increased body weight. We further validate our main in vivo findings using an Ins1-CreERT transgenic line and find that male mice have improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that β-cell insulin resistance in the form of reduced β-cell Insr contributes to hyperinsulinemia in the context of glucose stimulation, thereby improving glucose homeostasis in otherwise insulin sensitive sex, dietary and age contexts.en_US
dc.language.isoenen_US
dc.relation.ispartofNature Communicationsen_US
dc.relation.urlhttps://doi.org/10.1038/s41467-022-28039-8en_US
dc.rightsOpen Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2022en_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectDiabetesen_US
dc.titleBeta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistanceen_US
dc.typeJournal Articleen_US
dc.source.journaltitleNature communications
dc.source.volume13
dc.source.issue1
dc.source.beginpage735
dc.source.endpage
dc.source.countryCanada
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryCanada
dc.source.countryUnited States
dc.source.countryUnited States
dc.source.countryEngland
dc.identifier.journalNature communications
refterms.dateFOA2023-07-19T19:18:30Z
dc.contributor.departmentMedicineen_US
dc.contributor.departmentProgram in Molecular Medicineen_US


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Open Access: This article is licensed under a Creative Commons
Attribution 4.0 International License, which permits use, sharing,
adaptation, distribution and reproduction in any medium or format, as long as you give
appropriate credit to the original author(s) and the source, provide a link to the Creative
Commons license, and indicate if changes were made. The images or other third party
material in this article are included in the article’s Creative Commons license, unless
indicated otherwise in a credit line to the material. If material is not included in the
article’s Creative Commons license and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from
the copyright holder. To view a copy of this license, visit http://creativecommons.org/
licenses/by/4.0/.
© The Author(s) 2022
Except where otherwise noted, this item's license is described as Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/. © The Author(s) 2022