Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital

ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


  1. Epigenome- and Transcriptome-wide Changes in Muscle Stem Cells from Low Birth Weight Men

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. TCF7L2 Expression Is Regulated by Cell Differentiation and Overfeeding in Human Adipose Tissue

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Plasma ceramide levels are altered in low and normal birth weight men in response to short-term high-fat overfeeding

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • 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
Vis graf over relationer

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.

Udgave nummer3
Sider (fra-til)502-514
Antal sider13
StatusUdgivet - mar. 2019

Bibliografisk note

© 2019 by the American Diabetes Association.

ID: 59180101