PMID- 33581131
OWN - NLM
STAT- MEDLINE
DCOM- 20210527
LR  - 20210527
IS  - 1532-8600 (Electronic)
IS  - 0026-0495 (Linking)
VI  - 118
DP  - 2021 May
TI  - Quantitative phosphoproteomic analysis of IRS1 in skeletal muscle from men with 
      normal glucose tolerance or type 2 diabetes: A case-control study.
PG  - 154726
LID - S0026-0495(21)00026-3 [pii]
LID - 10.1016/j.metabol.2021.154726 [doi]
AB  - 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.
CI  - Copyright (c) 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Karlsson, Hakan K R
AU  - Karlsson HKR
AD  - Department of Molecular Medicine and Surgery, Integrative Physiology, Karolinska 
      Institutet, Stockholm 171 77, Sweden.
FAU - Kasahara, Akiko
AU  - Kasahara A
AD  - Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd., 
      1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
FAU - Ikeda, Mika
AU  - Ikeda M
AD  - Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd., 
      1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
FAU - Chibalin, Alexander V
AU  - Chibalin AV
AD  - Department of Molecular Medicine and Surgery, Integrative Physiology, Karolinska 
      Institutet, Stockholm 171 77, Sweden.
FAU - Harada, Jun
AU  - Harada J
AD  - Cardiovascular-Metabolics Research Laboratories, Daiichi Sankyo Co., Ltd., 
      1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
FAU - Ryden, Mikael
AU  - Ryden M
AD  - Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.
FAU - Krook, Anna
AU  - Krook A
AD  - Department of Physiology and Pharmacology, Integrative Physiology, Karolinska 
      Institutet, Stockholm 171 77, Sweden.
FAU - Kato, Mitsunori
AU  - Kato M
AD  - Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd., 
      1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
FAU - Kubota, Kazuishi
AU  - Kubota K
AD  - Discovery Science and Technology Department, Daiichi Sankyo RD Novare Co., Ltd., 
      1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
FAU - Zierath, Juleen R
AU  - Zierath JR
AD  - Department of Molecular Medicine and Surgery, Integrative Physiology, Karolinska 
      Institutet, Stockholm 171 77, Sweden; Department of Physiology and Pharmacology, 
      Integrative Physiology, Karolinska Institutet, Stockholm 171 77, Sweden. 
      Electronic address: Juleen.Zierath@ki.se.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210211
PL  - United States
TA  - Metabolism
JT  - Metabolism: clinical and experimental
JID - 0375267
RN  - 0 (IRS1 protein, human)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Phosphoproteins)
SB  - IM
MH  - Amino Acid Sequence
MH  - Biopsy
MH  - Case-Control Studies
MH  - Diabetes Mellitus, Type 2/*metabolism
MH  - *Glucose Tolerance Test
MH  - Humans
MH  - Insulin/metabolism
MH  - Insulin Receptor Substrate Proteins/*metabolism
MH  - Male
MH  - Middle Aged
MH  - Muscle, Skeletal/*metabolism/pathology
MH  - Phosphoproteins/*metabolism
MH  - Phosphorylation
MH  - Proteomics/*methods
MH  - Signal Transduction
OTO - NOTNLM
OT  - IRS1
OT  - Insulin resistance
OT  - Insulin signaling
OT  - Phosphoproteomics
OT  - Skeletal muscle
OT  - Type 2 diabetes
COIS- Declaration of competing interest No potential conflicts of interest relevant to 
      this article.
EDAT- 2021/02/14 06:00
MHDA- 2021/05/28 06:00
CRDT- 2021/02/13 20:09
PHST- 2020/11/19 00:00 [received]
PHST- 2021/01/23 00:00 [revised]
PHST- 2021/02/08 00:00 [accepted]
PHST- 2021/02/14 06:00 [pubmed]
PHST- 2021/05/28 06:00 [medline]
PHST- 2021/02/13 20:09 [entrez]
AID - S0026-0495(21)00026-3 [pii]
AID - 10.1016/j.metabol.2021.154726 [doi]
PST - ppublish
SO  - Metabolism. 2021 May;118:154726. doi: 10.1016/j.metabol.2021.154726. Epub 2021 
      Feb 11.