title: Endothelial Fcγ Receptor IIB Activation Blunts Insulin Delivery 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. FcγRIIB is expressed in numerous cell types including endothelium and B lymphocytes. Here we investigated how endothelial FcγRIIB influences glucose homeostasis, using 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 insulin delivery, and it was associated with blunted endothelial nitric oxide synthase (eNOS) activation in skeletal muscle. In culture, CRP suppressed endothelial cell insulin transcytosis via FcγRIIB activation and 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 delivery to skeletal muscle to cause insulin resistance. Thus, a series of mechanisms in endothelium that impairs insulin movement has been identified that may contribute to type 2 diabetes pathogenesis.
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Keiji
authors.initials: K
authors.lastname: Tanigaki
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Ken L
authors.initials: KL
authors.lastname: Chambliss
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Yuhanna
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Sacharidou
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Cardiovascular Research Center and Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Dmitriy N
authors.initials: DN
authors.lastname: Atochin
authors.affiliation: Cardiovascular Research Center and Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Huang
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX chieko.mineo@utsouthwestern.edu philip.shaul@utsouthwestern.edu.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX chieko.mineo@utsouthwestern.edu philip.shaul@utsouthwestern.edu.
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D001692:Biological Transport; D002097:C-Reactive Protein / Q000378:metabolism; D002417:Cattle; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: C080571:Fc gamma receptor IIB; D007328:Insulin; D017452:Receptors, IgG; D002097:C-Reactive Protein; D052250:Nitric Oxide Synthase Type III; D005947:Glucose