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Treatment of type 2 diabetes with the designer cytokine IC7Fc.
Findeisen, Maria; Allen, Tamara L; Henstridge, Darren C; Kammoun, Helene; Brandon, Amanda E; Baggio, Laurie L; Watt, Kevin I; Pal, Martin; Cron, Lena; Estevez, Emma; Yang, Christine; Kowalski, Greg M; O'Reilly, Liam; Egan, Casey; Sun, Emily; Thai, Le May; Krippner, Guy; Adams, Timothy E; Lee, Robert S; Grötzinger, Joachim; Garbers, Christoph; Risis, Steve; Kraakman, Michael J; Mellet, Natalie A; Sligar, James; Kimber, Erica T; Young, Richard L; Cowley, Michael A; Bruce, Clinton R; Meikle, Peter J; Baldock, Paul A; Gregorevic, Paul; Biden, Trevor J; Cooney, Gregory J; Keating, Damien J; Drucker, Daniel J; Rose-John, Stefan; Febbraio, Mark A.
Afiliação
  • Findeisen M; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • Allen TL; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Henstridge DC; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Kammoun H; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Brandon AE; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • Baggio LL; Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia.
  • Watt KI; Department of Medicine, Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • Pal M; Centre of Muscle Research, Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia.
  • Cron L; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • Estevez E; Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia.
  • Yang C; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • Kowalski GM; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • O'Reilly L; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Egan C; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Sun E; Institute for Physical Activity and Nutrition, Deakin University, Melbourne, Victoria, Australia.
  • Thai LM; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • Krippner G; Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
  • Adams TE; Molecular & Cellular Physiology Laboratory, Flinders University, Adelaide, South Australia, Australia.
  • Lee RS; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • Grötzinger J; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Garbers C; CSIRO Manufacturing, Melbourne, Victoria, Australia.
  • Risis S; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Kraakman MJ; Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany.
  • Mellet NA; Institut Für Pathologie, Otto von Guericke University, Magdeburg, Germany.
  • Sligar J; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Kimber ET; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Young RL; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Cowley MA; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • Bruce CR; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • Meikle PJ; Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia.
  • Baldock PA; Department of Physiology, Monash University, Melbourne, Victoria, Australia.
  • Gregorevic P; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Biden TJ; Institute for Physical Activity and Nutrition, Deakin University, Melbourne, Victoria, Australia.
  • Cooney GJ; Baker Heart & Diabetes Institute, Melbourne, Victoria, Australia.
  • Keating DJ; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • Drucker DJ; Centre of Muscle Research, Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia.
  • Rose-John S; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • Febbraio MA; The Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Nature ; 574(7776): 63-68, 2019 10.
Article em En | MEDLINE | ID: mdl-31554967
ABSTRACT
The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Recombinantes de Fusão / Imunoglobulina G / Citocinas / Diabetes Mellitus Tipo 2 / Receptor gp130 de Citocina Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Recombinantes de Fusão / Imunoglobulina G / Citocinas / Diabetes Mellitus Tipo 2 / Receptor gp130 de Citocina Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2019 Tipo de documento: Article