Disorders of glucose homeostasis are common in chronic kidney disease (CKD) and are associated with increased mortality, but the mechanisms of impaired insulin secretion in this disease remain unclear. Here, we tested the hypothesis that defective insulin secretion in CKD is caused by a direct effect of urea on pancreatic β cells. In a murine model in which CKD is induced by 5/6 nephrectomy (CKD mice), we observed defects in glucose-stimulated insulin secretion in vivo and in isolated islets. Similarly, insulin secretion was impaired in normal mouse and human islets that were cultured with disease-relevant concentrations of urea and in islets from normal mice treated orally with urea for 3 weeks. In CKD mouse islets as well as urea-exposed normal islets, we observed an increase in oxidative stress and protein
Laetitia Koppe, Elsa Nyam, Kevin Vivot, Jocelyn E. Manning Fox, Xiao-Qing Dai, Bich N. Nguyen, Dominique Trudel, Camille Attané, Valentine S. Moullé, Patrick E. MacDonald, Julien Ghislain, Vincent Poitout
CKD mice have defective glucose-stimulated insulin secretion in vivo.