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Type 2 diabetes ris...
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Schriever, Sonja C.German Center for Diabetes Research,Helmholtz Zentrum München
(författare)
Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity
- Artikel/kapitelEngelska2020
Förlag, utgivningsår, omfång ...
Nummerbeteckningar
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LIBRIS-ID:oai:lup.lub.lu.se:100e1df4-58ed-4489-833d-b935d9b29152
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https://lup.lub.lu.se/record/100e1df4-58ed-4489-833d-b935d9b29152URI
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https://doi.org/10.1172/JCI136363DOI
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Språk:engelska
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Sammanfattning på:engelska
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Klassifikation
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Ämneskategori:art swepub-publicationtype
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Ämneskategori:ref swepub-contenttype
Anmärkningar
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Recent genome-wide association studies (GWAS) identified DUSP8, encoding a dual-specificity phosphatase targeting mitogen-activated protein kinases, as a type 2 diabetes (T2D) risk gene. Here, we reveal that Dusp8 is a gatekeeper in the hypothalamic control of glucose homeostasis in mice and humans. Male, but not female, Dusp8 loss-of-function mice, either with global or corticotropin-releasing hormone neuron–specific deletion, had impaired systemic glucose tolerance and insulin sensitivity when exposed to high-fat diet (HFD). Mechanistically, we found impaired hypothalamic-pituitary-adrenal axis feedback, blunted sympathetic responsiveness, and chronically elevated corticosterone levels driven by hypothalamic hyperactivation of Jnk signaling. Accordingly, global Jnk1 ablation, AAV-mediated Dusp8 overexpression in the mediobasal hypothalamus, or metyrapone-induced chemical adrenalectomy rescued the impaired glucose homeostasis of obese male Dusp8-KO mice, respectively. The sex-specific role of murine Dusp8 in governing hypothalamic Jnk signaling, insulin sensitivity, and systemic glucose tolerance was consistent with functional MRI data in human volunteers that revealed an association of the DUSP8 rs2334499 risk variant with hypothalamic insulin resistance in men. Further, expression of DUSP8 was increased in the infundibular nucleus of T2D humans. In summary, our findings suggest the GWAS-identified gene Dusp8 as a novel hypothalamic factor that plays a functional role in the etiology of T2D.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Kabra, Dhiraj G.Helmholtz Zentrum München,German Center for Diabetes Research,Sun Pharma Advanced Research Company Ltd.
(författare)
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Pfuhlmann, KatrinTechnical University of Munich,Helmholtz Zentrum München,German Center for Diabetes Research
(författare)
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Baumann, PeterTechnical University of Munich,German Center for Diabetes Research,Helmholtz Zentrum München
(författare)
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Baumgart, Emily V.Helmholtz Zentrum München,German Center for Diabetes Research
(författare)
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Nagler, JoachimHelmholtz Zentrum München
(författare)
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Seebacher, FabianTechnical University of Munich,German Center for Diabetes Research,Helmholtz Zentrum München
(författare)
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Harrison, LukeHelmholtz Zentrum München,German Center for Diabetes Research,Technical University of Munich
(författare)
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Irmler, MartinHelmholtz Zentrum München
(författare)
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Kullmann, StephanieGerman Center for Diabetes Research,University of Tübingen
(författare)
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Corrêa-Da-Silva, FelipeUniversity of Amsterdam,Academic Medical Center of University of Amsterdam (AMC),Netherlands Institute for Neuroscience NIN - KNAW
(författare)
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Giesert, FlorianTechnical University of Munich,Helmholtz Zentrum München
(författare)
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Jain, RuchiLund University,Lunds universitet,Diabetes - öpatofysiologi,Forskargrupper vid Lunds universitet,Diabetes - Islet Patophysiology,Lund University Research Groups,German Center for Diabetes Research,Helmholtz Zentrum München(Swepub:lu)med-ruj
(författare)
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Schug, HannahSYNLAB Analytics & Services Switzerland AG
(författare)
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Castel, JulienUniversity of Paris-Saclay
(författare)
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Martinez, SarahUniversity of Paris-Saclay
(författare)
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Wu, MoyaHelmholtz Zentrum München
(författare)
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Häring, Hans UlrichUniversity of Tübingen,German Center for Diabetes Research
(författare)
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de Angelis, Martin HrabeHelmholtz Zentrum München,German Center for Diabetes Research,Technical University of Munich
(författare)
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Beckers, JohannesHelmholtz Zentrum München,German Center for Diabetes Research,Technical University of Munich
(författare)
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Müller, Timo D.University Hospital of Tubingen,German Center for Diabetes Research,Helmholtz Zentrum München
(författare)
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Stemmer, KerstinHelmholtz Zentrum München,German Center for Diabetes Research
(författare)
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Wurst, WolfgangGerman Center for Neurodegenerative Diseases (DZNE), Bonn,Munich Cluster for Systems Neurology,Helmholtz Zentrum München,Technical University of Munich
(författare)
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Rozman, JanInstitute of Molecular Genetics of the Academy of Sciences of the Czech Republic,German Center for Diabetes Research,Helmholtz Zentrum München
(författare)
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Nogueiras, RubenUniversity of Santiago de Compostela
(författare)
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de Angelis, MeriHelmholtz Zentrum München
(författare)
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Molkentin, Jeffery D.Cincinnati Children's Hospital Medical Center,University of Cincinnati
(författare)
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Krahmer, NatalieGerman Center for Diabetes Research,Helmholtz Zentrum München
(författare)
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Yi, Chun XiaNetherlands Institute for Neuroscience NIN - KNAW,Academic Medical Center of University of Amsterdam (AMC),University of Amsterdam
(författare)
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Schmidt, Mathias V.Max Planck Institute of Psychiatry
(författare)
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Luquet, SergeUniversity of Paris-Saclay
(författare)
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Heni, MartinUniversity of Tübingen,German Center for Diabetes Research,University Hospital of Tubingen
(författare)
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Tschöp, Matthias H.German Center for Diabetes Research,Helmholtz Zentrum München,Technical University of Munich
(författare)
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Pfluger, Paul T.Helmholtz Zentrum München,German Center for Diabetes Research,Technical University of Munich
(författare)
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German Center for Diabetes ResearchHelmholtz Zentrum München
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Journal of Clinical Investigation130:11, s. 6093-61080021-9738
Internetlänk
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Till lärosätets databas
- Av författaren/redakt...
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Schriever, Sonja ...
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Kabra, Dhiraj G.
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Pfuhlmann, Katri ...
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Baumann, Peter
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Baumgart, Emily ...
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Nagler, Joachim
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visa fler...
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Seebacher, Fabia ...
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Harrison, Luke
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Irmler, Martin
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Kullmann, Stepha ...
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Corrêa-Da-Silva, ...
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Giesert, Florian
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Jain, Ruchi
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Schug, Hannah
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Castel, Julien
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Martinez, Sarah
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Wu, Moya
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Häring, Hans Ulr ...
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de Angelis, Mart ...
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Beckers, Johanne ...
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Müller, Timo D.
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Stemmer, Kerstin
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Wurst, Wolfgang
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Rozman, Jan
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Nogueiras, Ruben
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de Angelis, Meri
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Molkentin, Jeffe ...
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Krahmer, Natalie
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Yi, Chun Xia
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Schmidt, Mathias ...
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Luquet, Serge
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Heni, Martin
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Tschöp, Matthias ...
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Pfluger, Paul T.
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visa färre...
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