C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser307 and Ser 612 in L6 myocytes, thereby impairing the insulin signalling pathway that promotes glucose transport.
OBJECTIVE
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.


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 Ser(307) and Ser(612), respectively. The stimulatory effects of hrCRP on IRS-1 phosphorylation at Ser(307) and Ser(612) 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 Tyr(632), 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
Our data suggest that hrCRP may cause insulin resistance by increasing IRS-1 phosphorylation at Ser(307) and Ser(612) 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.
D'Alessandris
C
C
Department of Internal Medicine, University of Rome-Tor Vergata, Rome, Italy.
Lauro
R
R
Presta
I
I
Sesti
G
G
D000818:Animals; D001692:Biological Transport; D002097:C-Reactive Protein / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D004731:Endotoxins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D032342:Muscle Cells / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction
D004731:Endotoxins; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D012694:Serine; D002097:C-Reactive Protein; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D005947:Glucose