Free Fatty Acid-Induced Reduction in Glucose Stimulated Insulin Secretion–Evidence for a Role of Oxidative Stress In Vitro and In Vivo

Abstract

Objective An important mechanism in the pathogenesis of type 2 diabetes in obese individuals is elevation of plasma FFA, which induce insulin resistance and chronically decrease β-cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in β-cell function.

Research Design and Methods We used an in vivo model of 48h i.v. oleate infusion in Wistar rats followed by hyperglycemic clamps, or islet secretion studies ex vivo, and in vitro models of 48h exposure to oleate in islets and MIN6 cells.

Results 48h Infusion of oleate decreased the insulin and C-peptide responses to a hyperglycemic clamp (p<0.01), an effect prevented by coinfusion of the antioxidants N-acetylcysteine and taurine. Similar to the findings in vivo, 48h infusion of oleate decreased glucose stimulated insulin secretion ex vivo (p<0.01), and induced oxidative stress (p<0.001) in isolated islets, effects prevented by coinfusion of the antioxidants N-acetylcysteine, taurine, or tempol. 48h infusion of olive oil induced oxidative stress (p<0.001) and decreased the insulin response of isolated islets similar to oleate (p<0.01). Islets exposed to oleate or palmitate and MIN6 cells exposed to oleate showed a decreased insulin response to high glucose and increased levels of oxidative stress (both p<0.001), effects prevented by taurine. Real-time RT-PCR showed increased mRNA levels of antioxidant genes in MIN6 cells following oleate exposure, an effect partially prevented by taurine.

Conclusions Our data are the first demonstration that oxidative stress plays a role in the decrease in β-cell secretory function induced by prolonged exposure to FFA, in vitro and in vivo.