ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations. / Graae, Anne-Sofie; Grarup, Niels; Ribel-Madsen, Rasmus; Lystbæk, Sara Hyldegaard; Boesgaard, Trine; Staiger, Harald; Fritsche, Andreas; Wellner, Niels; Sulek, Karolina; Kjølby, Mads Fuglsang; Backe, Marie Balslev; Chubanava, Sabina; Prats, Clara; Serup, Annette Karen Lundbeck; Birk, Jesper Bratz; Dubail, Johanne; Gillberg, Linn; Vienberg, Sara Gry; Nykjær, Anders; Kiens, Bente; Wojtaszewski, Jørgen; Larsen, Steen; Apte, Suneel S; Häring, Hans-Ulrich; Vaag, Allan; Zethelius, Björn; Pedersen, Oluf Borbye; Treebak, Jonas Thue; Hansen, Torben; Holst, Birgitte.

In: Diabetes, Vol. 68, No. 3, 2019, p. 502-514.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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

APA

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

Vancouver

Graae A-S, Grarup N, Ribel-Madsen R, Lystbæk SH, Boesgaard T, Staiger H et al. ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations. Diabetes. 2019;68(3):502-514. https://doi.org/10.2337/db18-0418

Author

Graae, Anne-Sofie ; Grarup, Niels ; Ribel-Madsen, Rasmus ; Lystbæk, Sara Hyldegaard ; Boesgaard, Trine ; Staiger, Harald ; Fritsche, Andreas ; Wellner, Niels ; Sulek, Karolina ; Kjølby, Mads Fuglsang ; Backe, Marie Balslev ; Chubanava, Sabina ; Prats, Clara ; Serup, Annette Karen Lundbeck ; Birk, Jesper Bratz ; Dubail, Johanne ; Gillberg, Linn ; Vienberg, Sara Gry ; Nykjær, Anders ; Kiens, Bente ; Wojtaszewski, Jørgen ; Larsen, Steen ; Apte, Suneel S ; Häring, Hans-Ulrich ; Vaag, Allan ; Zethelius, Björn ; Pedersen, Oluf Borbye ; Treebak, Jonas Thue ; Hansen, Torben ; Holst, Birgitte. / ADAMTS9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations. In: Diabetes. 2019 ; Vol. 68, No. 3. pp. 502-514.

Bibtex

@article{5d49892a4e1d41edace0d2d234300ac9,
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, 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.",
author = "Anne-Sofie Graae and Niels Grarup and Rasmus Ribel-Madsen and Lystb{\ae}k, {Sara Hyldegaard} and Trine Boesgaard and Harald Staiger and Andreas Fritsche and Niels Wellner and Karolina Sulek and Kj{\o}lby, {Mads Fuglsang} and Backe, {Marie Balslev} and Sabina Chubanava and Clara Prats and Serup, {Annette Karen Lundbeck} and Birk, {Jesper Bratz} and Johanne Dubail and Linn Gillberg and Vienberg, {Sara Gry} and Anders Nykj{\ae}r and Bente Kiens and J{\o}rgen Wojtaszewski and Steen Larsen and Apte, {Suneel S} and Hans-Ulrich H{\"a}ring and Allan Vaag and Bj{\"o}rn Zethelius and Pedersen, {Oluf Borbye} and Treebak, {Jonas Thue} and Torben Hansen and Birgitte Holst",
note = "CURIS 2019 NEXS 022",
year = "2019",
doi = "10.2337/db18-0418",
language = "English",
volume = "68",
pages = "502--514",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association",
number = "3",

}

RIS

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 -

ID: 211864208