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Free Fatty Acid–Induced Reduction in Glucose-Stimulated Insulin Secretion

Evidence for a Role of Oxidative Stress In Vitro and In Vivo

¹ Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
² Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
³ Department of Physiology, University of Toronto, Toronto, Ontario, Canada
⁴ Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
⁵ Toronto General Hospital, Toronto, Ontario, Canada
⁶ Mount Sinai Hospital, Toronto, Ontario, Canada

Address correspondence and reprint requests to Adria Giacca, 1 King’s College Circle, Medical Science Building, Room 3336, Toronto, ON, Canada. E-mail: adria.giacca{at}utoronto.ca

Abbreviations: CPT-1, carnitine palmitoyl transferase-1; DMEM, Dulbecco’s modified Eagle’s medium; FFA, free fatty acid; GINF, glucose infusion rate; GPx-1, gluthathione peroxidase-1; GSIS, glucose-stimulated insulin secretion; H₂DCF-DA, dihydro-dichlorofluorescein-diacetate; HO-1, heme oxygenase-1; KRB, Krebs-Ringer buffer; KRBH, KRB containing 10 mmol/l^–1 HEPES; ROS, reactive oxygen species; SOD, superoxide dismutase; tempol, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl; UCP, uncoupling protein

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 ß-cell function and mass. Our objective was to investigate the role of oxidative stress in FFA-induced decrease in ß-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 ß-cell secretory function induced by prolonged exposure to FFAs in vitro and in vivo.

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