Abstract 218: Endothelial Fc gamma Receptor IIB Activation Blunts Insulin Transport to Skeletal Muscle to Cause Insulin Resistance in Mice

Abstract

Modest elevations in C-reactive protein (CRP) are associated with type 2 diabetes. We previously revealed in mice that increased CRP causes insulin resistance, and mice globally deficient in the CRP receptor Fcγ receptor IIB (FcγRIIB) were protected from the disorder. Having determined that FcγRIIB is expressed in endothelium, here we investigated how endothelial FcγRIIB influences glucose homeostasis. Floxed FcγRIIB mice were crossed with VECadherin-driven Cre recombinase and CRP transgenic mice to yield mice with elevated CRP expressing or lacking endothelial FcγRIIB. Whereas increased CRP caused insulin resistance in mice expressing endothelial FcγRIIB, mice deficient in the endothelial receptor were protected. The insulin resistance with endothelial FcγRIIB activation was due to impaired skeletal muscle glucose uptake caused by attenuated skeletal muscle insulin delivery. In culture, CRP suppressed endothelial cell insulin transcytosis via FcγRIIB activation and endothelial NO synthase (eNOS) antagonism. Furthermore, in knock-in mice harboring constitutively-active eNOS, elevated CRP did not invoke insulin resistance. Collectively these findings reveal that by inhibiting eNOS, endothelial FcγRIIB activation by CRP blunts insulin transport to skeletal muscle to cause insulin resistance. Thus, a series of mechanisms in endothelium that impairs insulin transport has been identified that may contribute to type 2 diabetes pathogenesis.