Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. Glucagon Clearance is Preserved in Type 2 Diabetes

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Distinct Molecular Signatures of Clinical Clusters in People with Type 2 Diabetes: an IMI-RHAPSODY Study

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Differential DNA Methylation and Expression of miRNAs in Adipose Tissue From Twin Pairs Discordant for Type 2 Diabetes

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. The low-expression variant of FABP4 is associated with cardiovascular disease in type 1 diabetes

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Defining NASH from a multi-omics systems biology perspective

    Research output: Contribution to journalReviewResearchpeer-review

  3. Reply to “Quality control requirements for the correct annotation of lipidomics data”

    Research output: Contribution to journalLetterResearchpeer-review

  4. The role of vitamin C in epigenetic cancer therapy

    Research output: Contribution to journalReviewResearchpeer-review

  5. Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+ Tregs and improve metabolism

    Research output: Contribution to journalJournal articleResearchpeer-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
View graph of relations

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