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Type 2 diabetes ris...
Type 2 diabetes risk gene Dusp8 regulates hypothalamic Jnk signaling and insulin sensitivity
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- Schriever, Sonja C. (författare)
- German Center for Diabetes Research,Helmholtz Zentrum München
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- Kabra, Dhiraj G. (författare)
- Helmholtz Zentrum München,German Center for Diabetes Research,Sun Pharma Advanced Research Company Ltd.
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- Pfuhlmann, Katrin (författare)
- Technical University of Munich,Helmholtz Zentrum München,German Center for Diabetes Research
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- Baumann, Peter (författare)
- Technical University of Munich,German Center for Diabetes Research,Helmholtz Zentrum München
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- Baumgart, Emily V. (författare)
- Helmholtz Zentrum München,German Center for Diabetes Research
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- Nagler, Joachim (författare)
- Helmholtz Zentrum München
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- Seebacher, Fabian (författare)
- Technical University of Munich,German Center for Diabetes Research,Helmholtz Zentrum München
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- Harrison, Luke (författare)
- Helmholtz Zentrum München,German Center for Diabetes Research,Technical University of Munich
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- Irmler, Martin (författare)
- Helmholtz Zentrum München
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- Kullmann, Stephanie (författare)
- German Center for Diabetes Research,University of Tübingen
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- Corrêa-Da-Silva, Felipe (författare)
- University of Amsterdam,Academic Medical Center of University of Amsterdam (AMC),Netherlands Institute for Neuroscience NIN - KNAW
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- Giesert, Florian (författare)
- Technical University of Munich,Helmholtz Zentrum München
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- Jain, Ruchi (författare)
- Lund University,Lunds universitet,Diabetes - öpatofysiologi,Forskargrupper vid Lunds universitet,Diabetes - Islet Patophysiology,Lund University Research Groups,German Center for Diabetes Research,Helmholtz Zentrum München
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- Schug, Hannah (författare)
- SYNLAB Analytics & Services Switzerland AG
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- Castel, Julien (författare)
- University of Paris-Saclay
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- Martinez, Sarah (författare)
- University of Paris-Saclay
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- Wu, Moya (författare)
- Helmholtz Zentrum München
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- Häring, Hans Ulrich (författare)
- University of Tübingen,German Center for Diabetes Research
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- de Angelis, Martin Hrabe (författare)
- Helmholtz Zentrum München,German Center for Diabetes Research,Technical University of Munich
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- Beckers, Johannes (författare)
- Helmholtz Zentrum München,German Center for Diabetes Research,Technical University of Munich
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- Müller, Timo D. (författare)
- University Hospital of Tubingen,German Center for Diabetes Research,Helmholtz Zentrum München
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- Stemmer, Kerstin (författare)
- Helmholtz Zentrum München,German Center for Diabetes Research
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- Wurst, Wolfgang (författare)
- German Center for Neurodegenerative Diseases (DZNE), Bonn,Munich Cluster for Systems Neurology,Helmholtz Zentrum München,Technical University of Munich
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- Rozman, Jan (författare)
- Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic,German Center for Diabetes Research,Helmholtz Zentrum München
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- Nogueiras, Ruben (författare)
- University of Santiago de Compostela
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- de Angelis, Meri (författare)
- Helmholtz Zentrum München
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- Molkentin, Jeffery D. (författare)
- Cincinnati Children's Hospital Medical Center,University of Cincinnati
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- Krahmer, Natalie (författare)
- German Center for Diabetes Research,Helmholtz Zentrum München
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- Yi, Chun Xia (författare)
- Netherlands Institute for Neuroscience NIN - KNAW,Academic Medical Center of University of Amsterdam (AMC),University of Amsterdam
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- Schmidt, Mathias V. (författare)
- Max Planck Institute of Psychiatry
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- Luquet, Serge (författare)
- University of Paris-Saclay
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- Heni, Martin (författare)
- University of Tübingen,German Center for Diabetes Research,University Hospital of Tubingen
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- Tschöp, Matthias H. (författare)
- German Center for Diabetes Research,Helmholtz Zentrum München,Technical University of Munich
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- Pfluger, Paul T. (författare)
- Helmholtz Zentrum München,German Center for Diabetes Research,Technical University of Munich
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(creator_code:org_t)
- 2020
- 2020
- Engelska 16 s.
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 130:11, s. 6093-6108
- Relaterad länk:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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- 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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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Endokrinologi oc ...
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Journal of Clini ...
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Lunds universitet