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Diabetologia
Published in: Diabetologia 4/2007

01-04-2007 | Article

C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser307 and Ser612 in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport

Authors: C. D’Alessandris, R. Lauro, I. Presta, G. Sesti

Published in: Diabetologia | Issue 4/2007

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Abstract

Aims/hypothesis

C-reactive protein (CRP) is associated with insulin resistance and predicts development of type 2 diabetes. However, it is unknown whether CRP directly affects insulin signalling action. To this aim, we determined the effects of human recombinant CRP (hrCRP) on insulin signalling involved in glucose transport in L6 myotubes.

Materials and methods

L6 myotubes were exposed to endotoxin-free hrCRP and insulin-stimulated activation of signal molecules, glucose uptake and glycogen synthesis were assessed.

Results

We found that hrCRP stimulates both c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK)1/2 activity. These effects were paralleled by a concomitant increase in IRS-1 phosphorylation at Ser307 and Ser612, respectively. The stimulatory effects of hrCRP on IRS-1 phosphorylation at Ser307 and Ser612 were partially reversed by treatment with specific JNK and ERK1/2 inhibitors, respectively. Exposure of L6 myotubes to hrCRP reduced insulin-stimulated phosphorylation of IRS-1 at Tyr632, a site essential for engaging p85 subunit of phosphatidylinositol-3 kinase (PI-3K), protein kinase B (Akt) activation and glycogen synthase kinase-3 (GSK-3) phosphorylation. These events were accompanied by a decrease in insulin-stimulated glucose transporter (GLUT) 4 translocation to the plasma membrane, glucose uptake and glucose incorporation into glycogen. The inhibitory effects of hrCRP on insulin signalling and insulin-stimulated GLUT4 translocation were reversed by treatment with JNK inhibitor I and the mitogen-activated protein kinase inhibitor, PD98059.

Conclusions/interpretation

Our data suggest that hrCRP may cause insulin resistance by increasing IRS-1 phosphorylation at Ser307 and Ser612 via JNK and ERK1/2, respectively, leading to impaired insulin-stimulated glucose uptake, GLUT4 translocation, and glycogen synthesis mediated by the IRS-1/PI-3K/Akt/GSK-3 pathway.
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Metadata
Title
C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser307 and Ser612 in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport
Authors
C. D’Alessandris
R. Lauro
I. Presta
G. Sesti
Publication date
01-04-2007
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 4/2007
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-006-0522-y

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