ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations

Anne-Sofie Graae, Niels Grarup, Rasmus Ribel-Madsen, Sara Hyldegaard Lystbæk, Trine Boesgaard, Harald Staiger, Andreas Fritsche, Niels Wellner, Karolina Sulek, Mads Fuglsang Kjølby, Marie Balslev Backe, Sabina Chubanava, Clara Prats, Annette Karen Lundbeck Serup, Jesper Bratz Birk, Johanne Dubail, Linn Gillberg, Sara Gry Vienberg, Anders Nykjær, Bente KiensJørgen Wojtaszewski, Steen Larsen, Suneel S Apte, Hans-Ulrich Häring, Allan Vaag, Björn Zethelius, Oluf Borbye Pedersen, Jonas Thue Treebak, Torben Hansen, Birgitte Holst

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

17 Citationer (Scopus)

Abstract

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 b1 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondrial function in mouse muscle, which was observed 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.

OriginalsprogEngelsk
TidsskriftDiabetes
Vol/bind68
Udgave nummer3
Sider (fra-til)502-514
ISSN0012-1797
DOI
StatusUdgivet - 2019

Bibliografisk note

CURIS 2019 NEXS 022

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