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ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations
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 hu...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Diabetes Association
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385758/ https://www.ncbi.nlm.nih.gov/pubmed/30626608 http://dx.doi.org/10.2337/db18-0418 |
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author | Graae, Anne-Sofie Grarup, Niels Ribel-Madsen, Rasmus Lystbæk, Sara H. Boesgaard, Trine Staiger, Harald Fritsche, Andreas Wellner, Niels Sulek, Karolina Kjolby, Mads Backe, Marie Balslev Chubanava, Sabina Prats, Clara Serup, Annette K. Birk, Jesper B. Dubail, Johanne Gillberg, Linn Vienberg, Sara G. Nykjær, Anders Kiens, Bente Wojtaszewski, Jørgen F.P. Larsen, Steen Apte, Suneel S. Häring, Hans-Ulrich Vaag, Allan Zethelius, Björn Pedersen, Oluf Treebak, Jonas T. Hansen, Torben Holst, Birgitte |
author_facet | Graae, Anne-Sofie Grarup, Niels Ribel-Madsen, Rasmus Lystbæk, Sara H. Boesgaard, Trine Staiger, Harald Fritsche, Andreas Wellner, Niels Sulek, Karolina Kjolby, Mads Backe, Marie Balslev Chubanava, Sabina Prats, Clara Serup, Annette K. Birk, Jesper B. Dubail, Johanne Gillberg, Linn Vienberg, Sara G. Nykjær, Anders Kiens, Bente Wojtaszewski, Jørgen F.P. Larsen, Steen Apte, Suneel S. Häring, Hans-Ulrich Vaag, Allan Zethelius, Björn Pedersen, Oluf Treebak, Jonas T. Hansen, Torben Holst, Birgitte |
author_sort | Graae, Anne-Sofie |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6385758 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-63857582020-03-01 ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations Graae, Anne-Sofie Grarup, Niels Ribel-Madsen, Rasmus Lystbæk, Sara H. Boesgaard, Trine Staiger, Harald Fritsche, Andreas Wellner, Niels Sulek, Karolina Kjolby, Mads Backe, Marie Balslev Chubanava, Sabina Prats, Clara Serup, Annette K. Birk, Jesper B. Dubail, Johanne Gillberg, Linn Vienberg, Sara G. Nykjær, Anders Kiens, Bente Wojtaszewski, Jørgen F.P. Larsen, Steen Apte, Suneel S. Häring, Hans-Ulrich Vaag, Allan Zethelius, Björn Pedersen, Oluf Treebak, Jonas T. Hansen, Torben Holst, Birgitte Diabetes Metabolism 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. American Diabetes Association 2019-03 2019-01-09 /pmc/articles/PMC6385758/ /pubmed/30626608 http://dx.doi.org/10.2337/db18-0418 Text en © 2019 by the American Diabetes Association. http://www.diabetesjournals.org/content/licenseReaders may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license. |
spellingShingle | Metabolism Graae, Anne-Sofie Grarup, Niels Ribel-Madsen, Rasmus Lystbæk, Sara H. Boesgaard, Trine Staiger, Harald Fritsche, Andreas Wellner, Niels Sulek, Karolina Kjolby, Mads Backe, Marie Balslev Chubanava, Sabina Prats, Clara Serup, Annette K. Birk, Jesper B. Dubail, Johanne Gillberg, Linn Vienberg, Sara G. Nykjær, Anders Kiens, Bente Wojtaszewski, Jørgen F.P. Larsen, Steen Apte, Suneel S. Häring, Hans-Ulrich Vaag, Allan Zethelius, Björn Pedersen, Oluf Treebak, Jonas T. Hansen, Torben Holst, Birgitte ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations |
title | ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations |
title_full | ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations |
title_fullStr | ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations |
title_full_unstemmed | ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations |
title_short | ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations |
title_sort | adamts9 regulates skeletal muscle insulin sensitivity through extracellular matrix alterations |
topic | Metabolism |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6385758/ https://www.ncbi.nlm.nih.gov/pubmed/30626608 http://dx.doi.org/10.2337/db18-0418 |
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