Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease
Laetitia Koppe, … , Julien Ghislain, Vincent Poitout
Laetitia Koppe, … , Julien Ghislain, Vincent Poitout
Published August 15, 2016
Citation Information: J Clin Invest. 2016;126(9):3598-3612. https://doi.org/10.1172/JCI86181.
View: Text | PDF
Research Article Nephrology

Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease

Abstract

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 O-GlcNAcylation. Protein O-GlcNAcylation was also observed in pancreatic sections from CKD patients. Impairment of insulin secretion in both CKD mouse and urea-exposed islets was associated with reduced glucose utilization and activity of phosphofructokinase 1 (PFK-1), which could be reversed by inhibiting O-GlcNAcylation. Inhibition of O-GlcNAcylation also restored insulin secretion in both mouse models. These results suggest that insulin secretory defects associated with CKD arise from elevated circulating levels of urea that increase islet protein O-GlcNAcylation and impair glycolysis.

Authors

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

×

Figure 4

Exposure to urea in drinking water increases circulating urea levels and inhibits insulin secretion.

Options: View larger image (or click on image) Download as PowerPoint
Exposure to urea in drinking water increases circulating urea levels and...
(A) Urea consumption in drinking water (25 g/l) elevates blood urea levels independently of renal failure (n = 4–5). (B) Blood glucose and (C) corresponding insulin levels during IPGTTs (n = 3–4). (D) AUC during IPGTTs. (E) Insulin secretion shown as the percentage of insulin content assessed in 1-hour static incubations in response to 2.8 or 16.8 mmol/l (mM) glucose or 2.8 mmol/l glucose plus 35 mmol/l KCl in islets from mice after 3 weeks with or without urea in drinking water (n = 5–7). (F) GSIS (Δ2.8–16.8 mM) (n = 5–7). (G) Representative Western blot and (H) quantification for total protein O-GlcNAcylation in islets in mice with or without addition of urea to the drinking water for 3 weeks (n = 3–4). Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 versus vehicle; 2-way ANOVA with Bonferroni’s post-hoc test for A–C; 1-way ANOVA with Bonferroni’s post-hoc test for E; and Student’s t test for D, F, and H.