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  • Graae, Anne-SofieUniv Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Receptol, Copenhagen, Denmark (author)

ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations

  • Article/chapterEnglish2019

Publisher, publication year, extent ...

  • 2019-01-09
  • American Diabetes Association,2019
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-379022
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-379022URI
  • https://doi.org/10.2337/db18-0418DOI

Supplementary language notes

  • Language:English
  • Summary in:English

Part of subdatabase

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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 over expression resulted in decreased insulin signaling presumably mediated through alterations of the integrin 131 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondria! 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.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Grarup, NielsUniv Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark (author)
  • Ribel-Madsen, RasmusUniv Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark;Rigshosp, Dept Endocrinol, Copenhagen, Denmark;Novo Nordisk Fdn, Danish Diabet Acad, Odense, Denmark;Steno Diabet Ctr, Gentofte, Denmark (author)
  • Lystbaek, Sara H.Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Receptol, Copenhagen, Denmark (author)
  • Boesgaard, TrineUniv Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark (author)
  • Staiger, HaraldUniv Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany;German Ctr Diabet Res, Tubingen, Germany;Eberhard Karls Univ Tubingen, Dept Pharm & Biochem, Inst Pharmaceut Sci, Tubingen, Germany (author)
  • Fritsche, AndreasUniv Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany;German Ctr Diabet Res, Tubingen, Germany;Univ Tubingen Hosp, Dept Internal Med 4, Tubingen, Germany (author)
  • Wellner, NielsAarhus Univ, Lundbeck Fdn Res Ctr MIND, Danish Res Inst Translat Neurosci, Nord EMBL Partnership Mol Med,Dept Biomed, Aarhus, Denmark (author)
  • Sulek, KarolinaUniv Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Integrat Physiol, Copenhagen, Denmark (author)
  • Kjolby, MadsNovo Nordisk Fdn, Danish Diabet Acad, Odense, Denmark;Aarhus Univ, Lundbeck Fdn Res Ctr MIND, Danish Res Inst Translat Neurosci, Nord EMBL Partnership Mol Med,Dept Biomed, Aarhus, Denmark (author)
  • Backe, Marie BalslevUniv Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Receptol, Copenhagen, Denmark (author)
  • Chubanava, SabinaUniv Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Integrat Physiol, Copenhagen, Denmark (author)
  • Prats, ClaraUniv Copenhagen, Dept Biomed Sci, Ctr Hlth Aging, Xlab, Copenhagen, Denmark (author)
  • Serup, Annette K.Univ Copenhagen, Fac Sci, Dept Nutr Exercise & Sports, Sect Mol Physiol, Copenhagen, Denmark (author)
  • Birk, Jesper B.Univ Copenhagen, Fac Sci, Dept Nutr Exercise & Sports, Sect Mol Physiol, Copenhagen, Denmark (author)
  • Dubail, JohanneCleveland Clin, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44106 USA (author)
  • Gillberg, LinnSteno Diabet Ctr, Gentofte, Denmark (author)
  • Vienberg, Sara G.Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Integrat Physiol, Copenhagen, Denmark (author)
  • Nykjaer, AndersAarhus Univ, Lundbeck Fdn Res Ctr MIND, Danish Res Inst Translat Neurosci, Nord EMBL Partnership Mol Med,Dept Biomed, Aarhus, Denmark (author)
  • Kiens, BenteUniv Copenhagen, Fac Sci, Dept Nutr Exercise & Sports, Sect Mol Physiol, Copenhagen, Denmark (author)
  • Wojtaszewski, Jorgen F. P.Univ Copenhagen, Fac Sci, Dept Nutr Exercise & Sports, Sect Mol Physiol, Copenhagen, Denmark (author)
  • Larsen, SteenUniv Copenhagen, Dept Biomed Sci, Ctr Hlth Aging, Xlab, Copenhagen, Denmark (author)
  • Apte, Suneel S.Cleveland Clin, Lerner Res Inst, Dept Biomed Engn, Cleveland, OH 44106 USA (author)
  • Haering, Hans-UlrichUniv Tubingen, Helmholtz Ctr Munich, Inst Diabet Res & Metab Dis, Tubingen, Germany;German Ctr Diabet Res, Tubingen, Germany;Univ Tubingen Hosp, Dept Internal Med 4, Tubingen, Germany (author)
  • Vaag, AllanAstraZeneca, Cardiovasc & Metab Dis Translat Med Unit, Early Clin Dev Innovat Med & Early Dev Biotech Un, Gothenburg, Sweden (author)
  • Zethelius, BjörnUppsala universitet,Geriatrik(Swepub:uu)bjorzeth (author)
  • Pedersen, OlufUniv Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark (author)
  • Treebak, Jonas T.Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Integrat Physiol, Copenhagen, Denmark (author)
  • Hansen, TorbenUniv Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark (author)
  • Holst, BirgitteUniv Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Receptol, Copenhagen, Denmark (author)
  • Univ Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Receptol, Copenhagen, DenmarkUniv Copenhagen, Fac Hlth & Med Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Genet, Copenhagen, Denmark (creator_code:org_t)

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  • In:Diabetes: American Diabetes Association68:3, s. 502-5140012-17971939-327X

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