GW24-e1177 Uric acid induces oxidative stress and growth inhibition by activating adenosine monophosphate-activated protein kinase and extracellular signal-regulated kinase signal pathways in pancreatic β cells

Abstract

Objectives Hyperuricaemia is a disorder of purine metabolism, and is strongly associated with insulin resistance and abnormal glucose metabolism. As the producer of insulin, pancreatic β cells might be affected by elevated serum uric acid levels and contribute to the disregulated glucose metabolism. In this study, we investigated the effect of high uric acid on rat pancreatic β cell function. Methods Two rat clonal pancreatic β-cell lines, INS-1 and Rin-m5F, were co-cultured with concentrations of uric acid, with or without antioxidants, as well as extracellular signal-regulated kinase (ERK) and adenosine monophosphate-activated protein kinase (AMPK) inhibitors. Cell proliferation, reactive oxygen species (ROS), insulin secretion, and ERK and AMPK pathways were assessed by MTT, fluorescence staining, flow cytometry, ELISA and western blot analysis. Results Under high uric acid condition, proliferation of pancreatic β cells was inhibited, production of reactive oxygen species increased, and glucose stimulated insulin secretion was also compromised. Further examination on signal transduction pathways revealed that uric acid-induced ROS is involved in the activation of AMPK and ERK. Pharmacological inhibition of ERK activation rescued β cells from growth inhibition. More importantly, activation of ERK induced by uric acid is significantly diminished by AMPK inhibitor, indicating ERK as a downstream target of AMPK in response to high uric acid condition. Conclusions Our data indicate that high uric acid levels induce oxidative damage and inhibit growth of rat pancreatic β cells by activating the ERK and AMPK signal pathways. Hyperuricemia may contribute to abnormal glucose metabolism by causing oxidative damage and function inhibition of pancreatic β cells.