C-Reactive Protein Causes Insulin Resistance in Mice Through Fcγ Receptor IIB-Mediated Inhibition of Skeletal Muscle Glucose Delivery

Elevations in C-reactive protein (CRP) are associated with an increased risk of insulin resistance. Whether CRP plays a causal role is unknown. Here we show that CRP transgenic mice and wild-type mice administered recombinant CRP are insulin resistant. Mice lacking the inhibitory Fc gamma receptor IIB (Fc gamma RIIB) are protected from CRP-induced insulin resistance, and immunohistochemistry reveals that Fc gamma RIIB is expressed in skeletal muscle microvascular endothelium and is absent in skeletal muscle myocytes, adipocytes, and hepatocytes. The primary mechanism in glucose homeostasis disrupted by CRP is skeletal muscle glucose delivery, and CRP attenuates insulin-induced skeletal muscle blood flow. CRP does not impair skeletal muscle glucose delivery in Fc gamma RIIB-/- mice or in endothelial nitric oxide synthase knock-in mice with phosphomimetic modification of Ser1176, which is normally phosphorylated by insulin signaling to stimulate nitric oxide-mediated skeletal muscle blood flow and glucose delivery and is dephosphorylated by CRP/Fc gamma RIIB. Thus, CRP causes insulin resistance in mice through Fc gamma RIIB-mediated inhibition of skeletal muscle glucose delivery. Diabetes 62:721-731, 2013