A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes
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A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes. / Batista, Thiago M; Jayavelu, Ashok Kumar; Wewer Albrechtsen, Nicolai J; Iovino, Salvatore; Lebastchi, Jasmin; Pan, Hui; Dreyfuss, Jonathan M; Krook, Anna; Zierath, Juleen R; Mann, Matthias; Kahn, C Ronald.
In: Cell Metabolism, Vol. 32, No. 5, 2020, p. 844-859.e5.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - A Cell-Autonomous Signature of Dysregulated Protein Phosphorylation Underlies Muscle Insulin Resistance in Type 2 Diabetes
AU - Batista, Thiago M
AU - Jayavelu, Ashok Kumar
AU - Wewer Albrechtsen, Nicolai J
AU - Iovino, Salvatore
AU - Lebastchi, Jasmin
AU - Pan, Hui
AU - Dreyfuss, Jonathan M
AU - Krook, Anna
AU - Zierath, Juleen R
AU - Mann, Matthias
AU - Kahn, C Ronald
N1 - Copyright © 2020. Published by Elsevier Inc.
PY - 2020
Y1 - 2020
N2 - 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 in vitro 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.
AB - 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 in vitro 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.
U2 - 10.1016/j.cmet.2020.08.007
DO - 10.1016/j.cmet.2020.08.007
M3 - Journal article
C2 - 32888406
VL - 32
SP - 844-859.e5
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 5
ER -
ID: 248762180