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

J Clin Invest. 2016 Sep 1;126(9):3598-612. doi: 10.1172/JCI86181. Epub 2016 Aug 15.


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.

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Cyanates / chemistry
  • Disease Models, Animal
  • Exocytosis
  • Glucokinase / metabolism
  • Glucose / metabolism
  • Glucose Tolerance Test
  • Glycolysis*
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism
  • Kidney Failure, Chronic / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Stress
  • Phosphofructokinase-1 / metabolism
  • Reactive Oxygen Species / metabolism
  • Urea / chemistry*
  • Uremia / metabolism


  • Antioxidants
  • Cyanates
  • Insulin
  • Reactive Oxygen Species
  • Urea
  • Phosphofructokinase-1
  • Glucokinase
  • Glucose