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ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations

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Harvard

Graae, A-S, Grarup, N, Ribel-Madsen, R, Lystbæk, SH, Boesgaard, T, Staiger, H, Fritsche, A, Wellner, N, Sulek, K, Kjolby, M, Backe, MB, Chubanava, S, Prats, C, Serup, AK, Birk, JB, Dubail, J, Gillberg, L, Vienberg, SG, Nykjær, A, Kiens, B, Wojtaszewski, JFP, Larsen, S, Apte, SS, Häring, H-U, Vaag, A, Zethelius, B, Pedersen, O, Treebak, JT, Hansen, T & Holst, B 2019, 'ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations', Diabetes, bind 68, nr. 3, s. 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., Kjolby, M., Backe, M. B., Chubanava, S., Prats, C., Serup, A. K., 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

CBE

Graae A-S, Grarup N, Ribel-Madsen R, Lystbæk SH, Boesgaard T, Staiger H, Fritsche A, Wellner N, Sulek K, Kjolby M, Backe MB, Chubanava S, Prats C, Serup AK, Birk JB, Dubail J, Gillberg L, Vienberg SG, Nykjær A, Kiens B, Wojtaszewski JFP, Larsen S, Apte SS, Häring H-U, Vaag A, Zethelius B, Pedersen O, Treebak JT, Hansen T, 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

MLA

Vancouver

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. / ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations. I: Diabetes. 2019 ; Bind 68, Nr. 3. s. 502-514.

Bibtex

@article{3783b6b3943d42b9b3af316e2bad071e,
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 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.",
keywords = "ADAMTS9 Protein/genetics, Alleles, Animals, Extracellular Matrix/metabolism, Humans, Immunohistochemistry, Insulin/metabolism, Insulin Resistance/genetics, Integrin beta1/metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal/metabolism",
author = "Anne-Sofie Graae and Niels Grarup and Rasmus Ribel-Madsen and Lystb{\ae}k, {Sara H} and Trine Boesgaard and Harald Staiger and Andreas Fritsche and Niels Wellner and Karolina Sulek and Mads Kjolby and Backe, {Marie Balslev} and Sabina Chubanava and Clara Prats and Serup, {Annette K} and Birk, {Jesper B} and Johanne Dubail and Linn Gillberg and Vienberg, {Sara G} and Anders Nykj{\ae}r and Bente Kiens and Wojtaszewski, {J{\o}rgen F P} and Steen Larsen and Apte, {Suneel S} and Hans-Ulrich H{\"a}ring and Allan Vaag and Bj{\"o}rn Zethelius and Oluf Pedersen and Treebak, {Jonas T} and Torben Hansen and Birgitte Holst",
note = "{\textcopyright} 2019 by the American Diabetes Association.",
year = "2019",
month = mar,
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 H

AU - Boesgaard, Trine

AU - Staiger, Harald

AU - Fritsche, Andreas

AU - Wellner, Niels

AU - Sulek, Karolina

AU - Kjolby, Mads

AU - Backe, Marie Balslev

AU - Chubanava, Sabina

AU - Prats, Clara

AU - Serup, Annette K

AU - Birk, Jesper B

AU - Dubail, Johanne

AU - Gillberg, Linn

AU - Vienberg, Sara G

AU - Nykjær, Anders

AU - Kiens, Bente

AU - Wojtaszewski, Jørgen F P

AU - Larsen, Steen

AU - Apte, Suneel S

AU - Häring, Hans-Ulrich

AU - Vaag, Allan

AU - Zethelius, Björn

AU - Pedersen, Oluf

AU - Treebak, Jonas T

AU - Hansen, Torben

AU - Holst, Birgitte

N1 - © 2019 by the American Diabetes Association.

PY - 2019/3

Y1 - 2019/3

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 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.

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 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.

KW - ADAMTS9 Protein/genetics

KW - Alleles

KW - Animals

KW - Extracellular Matrix/metabolism

KW - Humans

KW - Immunohistochemistry

KW - Insulin/metabolism

KW - Insulin Resistance/genetics

KW - Integrin beta1/metabolism

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Muscle, Skeletal/metabolism

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: 59180101