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 Kiens; Jørgen Wojtaszewski; Steen Larsen; Suneel S Apte; Hans-Ulrich Häring; Allan Vaag; Björn Zethelius; Oluf Borbye Pedersen; Jonas Thue Treebak; Torben Hansen; Birgitte Holst

doi:10.2337/db18-0418

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

8 Citations (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—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 language	English
Journal	Diabetes
Volume	68
Issue number	3
Pages (from-to)	502-514
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db18-0418
Publication status	Published - 1 Mar 2019

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Graae, A.-S., Grarup, N., Ribel-Madsen, R., Lystbæk, S. H., Boesgaard, T., Staiger, H., Fritsche, A., Wellner, N., Sulek, K., Kjølby, M. F., Backe, M. B., Chubanava, S., Prats, C., Serup, A. K. L., Birk, J. B., Dubail, J., Gillberg, L., Vienberg, S. G., Nykjær, A., ... Holst, B. (2019). ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations. Diabetes, 68(3), 502-514. https://doi.org/10.2337/db18-0418

Graae, A-S, Grarup, N, Ribel-Madsen, R, Lystbæk, SH, Boesgaard, T, Staiger, H, Fritsche, A, Wellner, N, Sulek, K, Kjølby, MF, Backe, MB, Chubanava, S , Prats, C, Serup, AKL, Birk, JB, Dubail, J, Gillberg, L, Vienberg, SG, Nykjær, A, Kiens, B , Wojtaszewski, J , Larsen, S, Apte, SS, Häring, H-U, Vaag, A, Zethelius, B, Pedersen, OB , Treebak, JT , Hansen, T & Holst, B 2019, 'ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations', Diabetes, vol. 68, no. 3, pp. 502-514. https://doi.org/10.2337/db18-0418

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title = "ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations",

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—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.",

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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 - 2019/3/1

Y1 - 2019/3/1

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—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.

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—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.

U2 - 10.2337/db18-0418

DO - 10.2337/db18-0418

M3 - Journal article

C2 - 30626608

SN - 0012-1797

VL - 68

SP - 502

EP - 514

JO - Diabetes

JF - Diabetes

IS - 3

ER -

ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations

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