Quantitative phosphoproteomic analysis of IRS1 in skeletal muscle from men with normal glucose tolerance or type 2 diabetes: A case-control study

Research output: Contribution to journalJournal articlepeer-review

  • Håkan K.R. Karlsson
  • Akiko Kasahara
  • Mika Ikeda
  • Alexander V. Chibalin
  • Jun Harada
  • Mikael Rydén
  • Anna Krook
  • Mitsunori Kato
  • Kazuishi Kubota
  • Zierath, Juleen R

Background & aims: The physiological regulation and contribution of the multiple phosphorylation sites of insulin receptor substrate 1 (IRS1) to the pathogenesis of insulin resistance is unknown. Our aims were to map the phosphorylated motifs of IRS1 in skeletal muscle from people with normal glucose tolerance (NGT; n = 11) or type 2 diabetes mellitus (T2DM; n = 11). Methods: Skeletal muscle biopsies were obtained under fasted conditions or during a euglycemic clamp and IRS1 phosphorylation sites were identified by mass spectrometry. Results: We identified 33 phosphorylation sites in biopsies from fasted individuals, including 2 previously unreported sites ([Ser393] and [Thr1017]). In men with NGT and T2DM, insulin increased phosphorylation of 5 peptides covering 10 serine or threonine sites and decreased phosphorylation of 6 peptides covering 9 serine, threonine or tyrosine sites. Insulin-stimulation increased phosphorylation of 2 peptides, and decreased phosphorylation of 2 peptides only in men with NGT. Insulin increased phosphorylation of 2 peptides only in men with T2DM. Conclusions: Despite severe skeletal muscle insulin resistance, the pattern of IRS1 phosphorylation was not uniformly altered in T2DM. Our results contribute to the evolving understanding of the physiological regulation of insulin signaling and complement the comprehensive map of IRS1 phosphorylation in T2DM.

Original languageEnglish
Article number154726
Number of pages7
Publication statusPublished - 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors

    Research areas

  • Insulin resistance, Insulin signaling, IRS1, Phosphoproteomics, Skeletal muscle, Type 2 diabetes

ID: 272643004