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

Autor(es):Mostrar menos -

Batista, Thiago M. ^[1] ; Jayavelu, Ashok Kumar ^[2] ; Albrechtsen, Nicolai J. Wewer ^{[2, 3, 4]} ; Iovino, Salvatore ^[1] ; Lebastchi, Jasmin ^[1] ; Pan, Hui ^[5] ; Dreyfuss, Jonathan M. ^[5] ; Krook, Anna ^[6] ; Zierath, Juleen R. ^{[7, 8]} ; Mann, Matthias ^{[2, 3]} ; Kahn, C. Ronald ^[1]

Afiliação do(s) autor(es)

^[1] Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Harvard Med Sch, Boston, MA 02215 - USA

^[2] Max Planck Inst Biochem, Dept Prote & Signal Transduct, D-82152 Martinsried - Germany

^[3] Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth & Med Sci, DK-2200 Copenhagen - Denmark

^[4] Univ Copenhagen, Rigshosp, Dept Clin Biochem, DK-2100 Copenhagen - Denmark

^[5] Joslin Diabet Ctr, Bioinformat & Biostat Core, Harvard Med Sch, Boston, MA 02215 - USA

^[6] Karolinska Inst, Dept Physiol & Pharmacol, S-17177 Stockholm - Sweden

^[7] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, Fac Hlth & Med Sci, DK-2200 Copenhagen - Denmark

^[8] Karolinska Inst, Dept Mol Med & Surg, Sect Integrat Physiol, S-17176 Stockholm - Sweden

• Tipo de documento: Artigo Científico
• Fonte: Cell Metabolism; v. 32, n. 5, p. 844+, NOV 3 2020.
• Citações Web of Science: 1

Resumo

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. (AU)

• Processo FAPESP: 14/25370-8 - Caracterização de hepatócitos derivados de células tronco pluripotentes induzidas (iPSC) humanas de indivíduos resistentes a insulina
• Beneficiário: Thiago Martins Batista
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado