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

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 Nterminal 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/interpretation 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.

C-reactive protein impairs hepatic insulin sensitivity and insulin signaling in rats: Role of mitogen-activated protein kinases

“…In this current study, we, for the first time, demonstrate that hCRP can induce profound insulin resistance in rats in vivo, an effect on the liver but not on the peripheral tissues. In contrast to previous reports that hCRP impairs insulin action in L6 myocytes in vitro, 8 we did not observe an in vivo effect of hCRP on extrahepatic insulin sensitivity. Several factors my contribute to this discrepancy, including differences in hCRP concentration, the time course following hCRP treatment, the use of cell lines in the in vitro study, and, most important, variation in physiological conditions between in vivo and in vitro experiments.…”

“…Recent in vitro studies have shown that human CRP impairs insulin action in bovine vascular endothelial cells 10 and rat L6 myocytes. 8 However, the effects of hCRP on insulin sensitivity have not been examined in vivo. In this current study, we, for the first time, demonstrate that hCRP can induce profound insulin resistance in rats in vivo, an effect on the liver but not on the peripheral tissues.…”

“…[8][9][10] To date, in vivo data concerning the effect of hCRP on insulin action are still lacking. Recently published work shows that hCRP overexpression facilitates the development of insulin resistance and hepatosteatosis in high fat-fed mice 11 but the effect of hCRP on insulin action in liver tissue or in cultured hepatocytes has not previously been examined.…”

-Amyloid Oligomers Induce Phosphorylation of Tau and Inactivation of Insulin Receptor Substrate via c-Jun N-Terminal Kinase Signaling: Suppression by Omega-3 Fatty Acids and Curcumin

“…In peripheral tissues, both JNK and ERK phosphorylate IRS-1 at Ser307 (rodent equivalent for human Ser312) (Aguirre et al, 2000) and Ser616 (D'Alessandris et al, 2007). The resulting loss of IRS-1 coupling to PI3-K/Akt is predicted to activate another major tau kinase, GSK3␤, which is known to be activated by A␤ (Takashima et al, 1996;Ma et al, 2006;Hu et al, 2009).…”

Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells

“…IRS-1 contains multiple tyrosine-phosphorylation motifs and they mediate the metabolic and growthpromoting function of insulin [21][22][23]. IRS-1 also contains serine/threonine phosphorylation sites, such as IRS-1-S612, that when phosphorylated results in an inhibition of insulin signaling in the cell [24,25] and may indicate insulin resistance [26].…”