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

@article{citeulike:2973948, abstract = {OBJECTIVE--An important mechanism in the pathogenesis of type 2 diabetes in obese individuals is elevation of plasma free fatty acids (FFAs), which induce insulin resistance and chronically decrease {beta}-cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in {beta}-cell function. RESEARCH DESIGN AND METHODS--We used an in vivo model of 48-h intravenous oleate infusion in Wistar rats followed by hyperglycemic clamps or islet secretion studies ex vivo and in vitro models of 48-h exposure to oleate in islets and MIN6 cells. RESULTS--Forty-eight-hour 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 (NAC) and taurine. Similar to the findings in vivo, 48-h 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 NAC, taurine, or tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl). Forty-eight-hour 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 after 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 {beta}-cell secretory function induced by prolonged exposure to FFAs in vitro and in vivo. 10.2337/db07-0075}, author = {Oprescu, Andrei I. and Bikopoulos, George and Naassan, Anthony and Allister, Emma M. and Tang, Christine and Park, Edward and Uchino, Hiroshi and Lewis, Gary F. and Fantus, George I. and Rozakis-Adcock, Maria and Wheeler, Michael B. and Giacca, Adria }, citeulike-article-id = {2973948}, doi = {http://dx.doi.org/10.2337/db07-0075}, journal = {Diabetes}, keywords = {ffa, insulin, oxidative}, month = {December}, number = {12}, pages = {2927--2937}, posted-at = {2008-07-09 00:53:01}, priority = {3}, title = {Free Fatty Acid Induced Reduction in Glucose-Stimulated Insulin Secretion: Evidence for a Role of Oxidative Stress In Vitro and In Vivo}, url = {http://dx.doi.org/10.2337/db07-0075}, volume = {56}, year = {2007} }

TY - JOUR ID - citeulike:2973948 L3 - citeulike-article-id:2973948 TI - Free Fatty Acid Induced Reduction in Glucose-Stimulated Insulin Secretion: Evidence for a Role of Oxidative Stress In Vitro and In Vivo JF - Diabetes VL - 56 IS - 12 SP - 2927 EP - 2937 N2 - OBJECTIVE--An important mechanism in the pathogenesis of type 2 diabetes in obese individuals is elevation of plasma free fatty acids (FFAs), which induce insulin resistance and chronically decrease {beta}-cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in {beta}-cell function. RESEARCH DESIGN AND METHODS--We used an in vivo model of 48-h intravenous oleate infusion in Wistar rats followed by hyperglycemic clamps or islet secretion studies ex vivo and in vitro models of 48-h exposure to oleate in islets and MIN6 cells. RESULTS--Forty-eight-hour 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 (NAC) and taurine. Similar to the findings in vivo, 48-h 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 NAC, taurine, or tempol (4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl). Forty-eight-hour 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 after 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 {beta}-cell secretory function induced by prolonged exposure to FFAs in vitro and in vivo. 10.2337/db07-0075 KW - ffa KW - insulin KW - oxidative AU - Oprescu, Andrei AU - Bikopoulos, George AU - Naassan, Anthony AU - Allister, Emma AU - Tang, Christine AU - Park, Edward AU - Uchino, Hiroshi AU - Lewis, Gary AU - Fantus, George AU - Rozakis-Adcock, Maria AU - Wheeler, Michael AU - Giacca, Adria PY - 2007/12/01/ UR - http://dx.doi.org/10.2337/db07-0075 ER -