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

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

doi:10.1016/j.metabol.2021.154726

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

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

^*Corresponding author af dette arbejde

Zierath Group

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

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Abstract

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.

Originalsprog	Engelsk
Artikelnummer	154726
Tidsskrift	Metabolism
Vol/bind	118
Antal sider	7
ISSN	0026-0495
DOI	https://doi.org/10.1016/j.metabol.2021.154726
Status	Udgivet - 2021

Bibliografisk note

Publisher Copyright:
© 2021 The Authors

Finansiering

The cost of human proteomics study was supported by a grant from Daiichi Sankyo Co., Ltd. This work was supported by grants from the Swedish Diabetes Foundation ( DIA2018-357 ; DIA2018-336 ), Swedish Research Council ( 2015-00165 , 2018-02389 ), the Strategic Research Programme in Diabetes at Karolinska Institutet ( 2009-1068 ), the Knut and Alice Wallenberg Foundation ( 2018-0094 ), the Novo Nordisk Foundation ( NNF17OC0030088 ) and the Stockholm County Council ( SLL20190173 ). Juleen R. Zierath is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors thank Asuka Naito, Masanori Izumi, Tatsuo Tanimoto, Futoshi Nara, Akira Shinagawa and Fujio Isono for valuable advice and support, Yuri Hasui, Tatsuya Inoue, and Hiroshi Katsuno for technical support. The cost of human proteomics study was supported by a grant from Daiichi Sankyo Co. Ltd. This work was supported by grants from the Swedish Diabetes Foundation (DIA2018-357; DIA2018-336), Swedish Research Council (2015-00165, 2018-02389), the Strategic Research Programme in Diabetes at Karolinska Institutet (2009-1068), the Knut and Alice Wallenberg Foundation (2018-0094), the Novo Nordisk Foundation (NNF17OC0030088) and the Stockholm County Council (SLL20190173). Juleen R. Zierath is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. H.K.R.K. researched data and wrote the manuscript; A.K. researched data and reviewed/edited the manuscript; M.I. researched data and reviewed/edited the manuscript; A.C. researched data and reviewed/edited the manuscript; J.H. contributed to the study design and reviewed/edited the manuscript; M.R. contributed to the study design, researched data and reviewed/edited the manuscript; A.K. contributed to the study design, and wrote the manuscript; M.K. researched data; K?K contributed to the study design, researched data and reviewed/edited the manuscript; J.R.Z. contributed to the study design, and wrote the manuscript.

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10.1016/j.metabol.2021.154726Licens: CC BY

Quantitative phosphoproteomic analysis of IRS1 in skeletal muscle from men with normal glucose tolerance or type 2 diabetes: A case-control studyForlagets udgivne version, 705 KBLicens: CC BY

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@article{ce6a3bd677b84c32ae6b621776e37a4e,

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

abstract = "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.",

keywords = "Insulin resistance, Insulin signaling, IRS1, Phosphoproteomics, Skeletal muscle, Type 2 diabetes",

author = "Karlsson, \{H{\aa}kan K.R.\} and Akiko Kasahara and Mika Ikeda and Chibalin, \{Alexander V.\} and Jun Harada and Mikael Ryd{\'e}n and Anna Krook and Mitsunori Kato and Kazuishi Kubota and Zierath, \{Juleen R.\}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

doi = "10.1016/j.metabol.2021.154726",

language = "English",

volume = "118",

journal = "Metabolism",

issn = "0026-0495",

publisher = "W.B. Saunders",

}

TY - JOUR

T1 - Quantitative phosphoproteomic analysis of IRS1 in skeletal muscle from men with normal glucose tolerance or type 2 diabetes

T2 - A case-control study

AU - Karlsson, Håkan K.R.

AU - Kasahara, Akiko

AU - Ikeda, Mika

AU - Chibalin, Alexander V.

AU - Harada, Jun

AU - Rydén, Mikael

AU - Krook, Anna

AU - Kato, Mitsunori

AU - Kubota, Kazuishi

AU - Zierath, Juleen R.

PY - 2021

Y1 - 2021

N2 - 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.

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.

KW - Insulin resistance

KW - Insulin signaling

KW - IRS1

KW - Phosphoproteomics

KW - Skeletal muscle

KW - Type 2 diabetes

U2 - 10.1016/j.metabol.2021.154726

DO - 10.1016/j.metabol.2021.154726

M3 - Journal article

C2 - 33581131

AN - SCOPUS:85101581407

SN - 0026-0495

VL - 118

JO - Metabolism

JF - Metabolism

M1 - 154726

ER -