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  A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes.

Batista, T. M., Jayavelu, A. K., Wewer Albrechtsen, N. J., Iovino, S., Lebastchi, J., Pan, H., et al. (2020). A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes. Cell Metabolism, 32(5), 844-859.e5. doi:10.1016/j.cmet.2020.08.007.

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 Creators:
Batista, Thiago M1, Author
Jayavelu, Ashok Kumar2, Author              
Wewer Albrechtsen, Nicolai J.2, Author              
Iovino, Salvatore1, Author
Lebastchi, Jasmin1, Author
Pan, Hui1, Author
Dreyfuss, Jonathan M1, Author
Krook, Anna1, Author
Zierath, Juleen R1, Author
Mann, Matthias2, Author              
Kahn, C Ronald1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: chromatin remodeling; glucose transport; iPSC; insulin resistance; mRNA splicing; mitochondrial oxidation; phosphoproteomics; skeletal muscle; type 2 diabetes; vesicle trafficking
 Abstract: Skeletal muscle insulin resistance is the earliest defect in type 2 diabetes (T2D), preceding and predicting disease development. To what extent this reflects a primary defect or is secondary to tissue cross talk due to changes in hormones or circulating metabolites is unknown. To address this question, we have developed an invitro disease-in-a-dish model using iPS cells from T2D patients differentiated into myoblasts (iMyos). We find that T2D iMyos in culture exhibit multiple defects mirroring human disease, including an altered insulin signaling, decreased insulin-stimulated glucose uptake, and reduced mitochondrial oxidation. More strikingly, global phosphoproteomic analysis reveals a multidimensional network of signaling defects in T2D iMyos going beyond the canonical insulin-signaling cascade, including proteins involved in regulation of Rho GTPases, mRNA splicing and/or processing, vesicular trafficking, gene transcription, and chromatin remodeling. These cell-autonomous defects and the dysregulated network of protein phosphorylation reveal a new dimension in the cellular mechanisms underlying the fundamental defects in T2D. Copyright © 2020. Published by Elsevier Inc.

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Language(s): eng - English
 Dates: 2020-092020-11
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 32888406
DOI: 10.1016/j.cmet.2020.08.007
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Title: Cell Metabolism
  Other : Cell Metabolism
Source Genre: Journal
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Publ. Info: Cambridge, MA : Cell Press
Pages: - Volume / Issue: 32 (5) Sequence Number: - Start / End Page: 844 - 859.e5 Identifier: ISSN: 1550-4131
CoNE: https://pure.mpg.de/cone/journals/resource/111088195284928