Endothelial fcg receptor IIB activation blunts insulin delivery to skeletal muscle to cause insulin resistance in mice

Keiji Tanigaki, Ken L. Chambliss, Ivan S. Yuhanna, Anastasia Sacharidou, Mohamed Ahmed, Dmitriy N. Atochin, Paul L. Huang, Philip W. Shaul, Chieko Mineo

Research output: Contribution to journalArticle

12 Citations (Scopus)

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 Fcg receptor IIB (FcgRIIB) were protected from the disorder. FcgRIIB is expressed in numerous cell types including endothelium and B lymphocytes. Here we investigated how endothelial FcgRIIB influences glucose homeostasis, using mice with elevated CRP expressing or lacking endothelial FcgRIIB. Whereas increased CRP caused insulin resistance in mice expressing endothelial FcgRIIB, mice deficient in the endothelial receptor were protected. The insulin resistance with endothelial FcgRIIB 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 FcgRIIB 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 FcgRIIB 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.

Original languageEnglish
Pages (from-to)1996-2005
Number of pages10
JournalDiabetes
Volume65
Issue number7
DOIs
Publication statusPublished - 1 Jul 2016
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Tanigaki, K., Chambliss, K. L., Yuhanna, I. S., Sacharidou, A., Ahmed, M., Atochin, D. N., Huang, P. L., Shaul, P. W., & Mineo, C. (2016). Endothelial fcg receptor IIB activation blunts insulin delivery to skeletal muscle to cause insulin resistance in mice. Diabetes, 65(7), 1996-2005. https://doi.org/10.2337/db15-1605