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Rigshospitalet - a part of Copenhagen University Hospital
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ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations

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  • Anne-Sofie Graae
  • Niels Grarup
  • Rasmus Ribel-Madsen
  • Sara H Lystbæk
  • Trine Boesgaard
  • Harald Staiger
  • Andreas Fritsche
  • Niels Wellner
  • Karolina Sulek
  • Mads Kjolby
  • Marie Balslev Backe
  • Sabina Chubanava
  • Clara Prats
  • Annette K Serup
  • Jesper B Birk
  • Johanne Dubail
  • Linn Gillberg
  • Sara G Vienberg
  • Anders Nykjær
  • Bente Kiens
  • Jørgen F P Wojtaszewski
  • Steen Larsen
  • Suneel S Apte
  • Hans-Ulrich Häring
  • Allan Vaag
  • Björn Zethelius
  • Oluf Pedersen
  • Jonas T Treebak
  • Torben Hansen
  • Birgitte Holst
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The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking Adamts9 selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective overexpression resulted in decreased insulin signaling presumably mediated through alterations of the integrin β1 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondrial function in mouse muscle-an observation found to be of translational character because humans carrying the ADAMTS9 risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.

Original languageEnglish
JournalDiabetes
Volume68
Issue number3
Pages (from-to)502-514
Number of pages13
ISSN0012-1797
DOIs
Publication statusPublished - Mar 2019

    Research areas

  • ADAMTS9 Protein/genetics, Alleles, Animals, Extracellular Matrix/metabolism, Humans, Immunohistochemistry, Insulin/metabolism, Insulin Resistance/genetics, Integrin beta1/metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal/metabolism

ID: 59180101