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Truncation of Pik3r1 causes severe insulin resistance uncoupled from obesity and dyslipidaemia by increased energy expenditure

  • Kwok, Albert1, 2
  • Zvetkova, Ilona1, 2
  • Virtue, Sam1, 2
  • Luijten, Ineke3
  • Huang-Doran, Isabel1, 2
  • Tomlinson, Patsy1, 2
  • Bulger, David A.1, 2
  • West, James4
  • Murfitt, Steven4
  • Griffin, Julian4, 5
  • Alam, Rafeah6
  • Hart, Daniel1, 2
  • Knox, Rachel1, 2
  • Voshol, Peter7
  • Vidal-Puig, Antonio1, 2
  • Jensen, Jørgen8
  • O'Rahilly, Stephen1, 2
  • Semple, Robert K.3, 1, 2
  • 1 The University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
  • 2 MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, UK
  • 3 Centre for Cardiovascular Science, University of Edinburgh, 47 Little France Crescent, Edinburgh, UK
  • 4 Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, UK
  • 5 Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Medicine, Imperial College London, The Sir Alexander Fleming Building, London, UK
  • 6 Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge, UK
  • 7 Louis Bolk Institute, Kosterijland 3-5, NL-3981 AJ, Bunnik, the Netherlands
  • 8 Department of Physical Performance, Norwegian School of Sport Sciences, P.O. Box 4014, Ulleval Stadion, 0806 Oslo, Norway
Published Article
Molecular Metabolism
Elsevier BV
Publication Date
May 19, 2020
DOI: 10.1016/j.molmet.2020.101020
PMID: 32439336
PMCID: PMC7385515
PubMed Central


• SHORT syndrome features insulin resistance and reduced adiposity without dyslipidaemia and fatty liver. • A mouse model with a pathogenic human PI 3-Kinase mutation recapitulates this uncoupling. • Surprisingly, no adipose injury nor increased liver de novo lipogenesis is seen. • Energy expenditure is increased, causing resistance to diet-induced obesity. • This increases evidence for some beneficial metabolic effects of PI 3-Kinase inhibition.

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