Elevated circulating free fatty acids levels causing pancreatic islet cell dysfunction through oxidative stress

Abstract

Elevated plasma free fatty acids (FFA) concentration is predictive of the conversion from normal glucose tolerance and impaired glucose tolerance to diabetes. To evaluate the effects of prolonged exposure to FFA on basal and glucose-stimulated insulin secretion (GSIS) of pancreatic beta-cell, and to investigate the role of oxidative stress in FFA-induced decrease in beta-cell function. Rats were assigned to 3 groups and underwent 96-h infusions of normal saline (NS), intralipid plus heparin (IH), or intralipid plus heparin and N-acetylcysteine (IH+NAC). The plasma insulin, malonyldialdehyde (MDA), reduced glutathione (GSH), and oxidized glutathione (GSSG) were measured. In vivo intravenous glucose tolerance test (IVGTT) and ex vivo isolated pancreatic tissues perfusion were performed. In IH group GSIS both in IVGTT and perifused pancreatic tissues were impaired (p<0.05), the GSH/GSSG ratio was declined and MDA levels increased (p<0.05), the volume density score of nuclear factor kappaB and inducible nitric oxide synthase in pancreatic islets were increased compared to the NS group (p<0.01). In IH+NAC group, NAC intervention partly restored the GSH/GSSG ratio and MDA level, and improved FFA induced GSIS impairment. Elevated circulating FFA levels may contribute to causing the abnormalities of pancreatic islet cell function through active oxidative stress and oxidative stress-sensitive signaling pathway, which may play a key role in the development of impaired insulin secretion seen in obese Type 2 diabetes.