TY - JOUR
T1 - ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations
AU - Graae, Anne-Sofie
AU - Grarup, Niels
AU - Ribel-Madsen, Rasmus
AU - Lystbæk, Sara Hyldegaard
AU - Boesgaard, Trine
AU - Staiger, Harald
AU - Fritsche, Andreas
AU - Wellner, Niels
AU - Sulek, Karolina
AU - Kjølby, Mads Fuglsang
AU - Backe, Marie Balslev
AU - Chubanava, Sabina
AU - Prats, Clara
AU - Serup, Annette Karen Lundbeck
AU - Birk, Jesper Bratz
AU - Dubail, Johanne
AU - Gillberg, Linn
AU - Vienberg, Sara Gry
AU - Nykjær, Anders
AU - Kiens, Bente
AU - Wojtaszewski, Jørgen
AU - Larsen, Steen
AU - Apte, Suneel S
AU - Häring, Hans-Ulrich
AU - Vaag, Allan
AU - Zethelius, Björn
AU - Pedersen, Oluf Borbye
AU - Treebak, Jonas Thue
AU - Hansen, Torben
AU - Holst, Birgitte
N1 - CURIS 2019 NEXS 022
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
U2 - 10.2337/db18-0418
DO - 10.2337/db18-0418
M3 - Journal article
C2 - 30626608
VL - 68
SP - 502
EP - 514
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 3
ER -