Free fatty acid-induced reduction in glucose-stimulated insulin secretion: evidence for a role of oxidative stress in vitro and in vivo.
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.


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.
Oprescu
Andrei I
AI
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Bikopoulos
George
G
Naassan
Anthony
A
Allister
Emma M
EM
Tang
Christine
C
Park
Edward
E
Uchino
Hiroshi
H
Lewis
Gary F
GF
Fantus
I George
IG
Rozakis-Adcock
Maria
M
Wheeler
Michael B
MB
Giacca
Adria
A
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D009765:Obesity / Q000097:blood; D019301:Oleic Acid / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013654:Taurine / Q000494:pharmacology
D000975:Antioxidants; D001786:Blood Glucose; D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D012333:RNA, Messenger; D013654:Taurine; D019301:Oleic Acid; D005947:Glucose; D000111:Acetylcysteine