TY - JOUR
T1 - Global IRS-1 phosphorylation analysis in insulin resistance
AU - Langlais, P.
AU - Yi, Z.
AU - Finlayson, J.
AU - Luo, M.
AU - Mapes, R.
AU - De Filippis, E.
AU - Meyer, C.
AU - Plummer, E.
AU - Tongchinsub, P.
AU - Mattern, M.
AU - Mandarino, L. J.
N1 - Funding Information:
Acknowledgements This work was supported in part by NIH grants R01DK47936 (L.J. Mandarino), R01DK66483 (L.J. Mandarino), R01DK081750 (Z. Yi), 5F32DK078460-02 (P. Langlais) and a VA Merit Review grant (C. Meyer) and by the Office of Research and Development, Medical Research Service, Department of Veterans Affairs. We would like to thank Marv Ruona for his help in preparing the summary figure for this article.
PY - 2011/11
Y1 - 2011/11
N2 - Aims/hypothesis: IRS-1 serine phosphorylation is often elevated in insulin resistance models, but confirmation in vivo in humans is lacking. We therefore analysed IRS-1 phosphorylation in human muscle in vivo. Methods: We used HPLC-electrospray ionisation (ESI)-MS/MS to quantify IRS-1 phosphorylation basally and after insulin infusion in vastus lateralis muscle from lean healthy, obese non-diabetic and type 2 diabetic volunteers. Results: Basal Ser323 phosphorylation was increased in type 2 diabetic patients (2.1 ± 0.43, p ≤ 0.05, fold change vs lean controls). Thr495 phosphorylation was decreased in type 2 diabetic patients (p ≤ 0.05). Insulin increased IRS-1 phosphorylation at Ser527 (1.4 ± 0.17, p ≤ 0.01, fold change, 60 min after insulin infusion vs basal) and Ser531 (1.3 ± 0.16, p ≤ 0.01, fold change, 60 min after insulin infusion vs basal) in the lean controls and suppressed phosphorylation at Ser348 (0.56 ± 0.11, p ≤ 0.01, fold change, 240 min after insulin infusion vs basal), Thr446 (0.64 ± 0.16, p ≤ 0.05, fold change, 60 min after insulin infusion vs basal), Ser1100 (0.77 ± 0.22, p ≤ 0.05, fold change, 240 min after insulin infusion vs basal) and Ser1142 (1.3 ± 0.2, p ≤ 0.05, fold change, 60 min after insulin infusion vs basal). Conclusions/interpretation: We conclude that, unlike some aspects of insulin signalling, the ability of insulin to increase or suppress certain IRS-1 phosphorylation sites is intact in insulin resistance. However, some IRS-1 phosphorylation sites do not respond to insulin, whereas other Ser/Thr phosphorylation sites are either increased or decreased in insulin resistance.
AB - Aims/hypothesis: IRS-1 serine phosphorylation is often elevated in insulin resistance models, but confirmation in vivo in humans is lacking. We therefore analysed IRS-1 phosphorylation in human muscle in vivo. Methods: We used HPLC-electrospray ionisation (ESI)-MS/MS to quantify IRS-1 phosphorylation basally and after insulin infusion in vastus lateralis muscle from lean healthy, obese non-diabetic and type 2 diabetic volunteers. Results: Basal Ser323 phosphorylation was increased in type 2 diabetic patients (2.1 ± 0.43, p ≤ 0.05, fold change vs lean controls). Thr495 phosphorylation was decreased in type 2 diabetic patients (p ≤ 0.05). Insulin increased IRS-1 phosphorylation at Ser527 (1.4 ± 0.17, p ≤ 0.01, fold change, 60 min after insulin infusion vs basal) and Ser531 (1.3 ± 0.16, p ≤ 0.01, fold change, 60 min after insulin infusion vs basal) in the lean controls and suppressed phosphorylation at Ser348 (0.56 ± 0.11, p ≤ 0.01, fold change, 240 min after insulin infusion vs basal), Thr446 (0.64 ± 0.16, p ≤ 0.05, fold change, 60 min after insulin infusion vs basal), Ser1100 (0.77 ± 0.22, p ≤ 0.05, fold change, 240 min after insulin infusion vs basal) and Ser1142 (1.3 ± 0.2, p ≤ 0.05, fold change, 60 min after insulin infusion vs basal). Conclusions/interpretation: We conclude that, unlike some aspects of insulin signalling, the ability of insulin to increase or suppress certain IRS-1 phosphorylation sites is intact in insulin resistance. However, some IRS-1 phosphorylation sites do not respond to insulin, whereas other Ser/Thr phosphorylation sites are either increased or decreased in insulin resistance.
KW - IRS-1
KW - Insulin resistance
KW - Mass spectrometry
KW - Phosphorylation
KW - Serine
KW - Threonine
KW - Type 2 diabetes
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U2 - 10.1007/s00125-011-2271-9
DO - 10.1007/s00125-011-2271-9
M3 - Article
C2 - 21850561
AN - SCOPUS:80054707320
SN - 0012-186X
VL - 54
SP - 2878
EP - 2889
JO - Diabetologia
JF - Diabetologia
IS - 11
ER -