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

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

  1. Andrei I. Oprescu1,
  2. George Bikopoulos2,
  3. Anthony Naassan3,
  4. Emma M. Allister3,
  5. Christine Tang3,
  6. Edward Park3,
  7. Hiroshi Uchino3,
  8. Gary F. Lewis345,
  9. I. George Fantus346,
  10. Maria Rozakis-Adcock2,
  11. Michael B. Wheeler3 and
  12. Adria Giacca134
  1. 1Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
  2. 2Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  3. 3Department of Physiology, University of Toronto, Toronto, Ontario, Canada
  4. 4Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  5. 5Toronto General Hospital, Toronto, Ontario, Canada
  6. 6Mount Sinai Hospital, Toronto, Ontario, Canada
  1. 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

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 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 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 β-cell secretory function induced by prolonged exposure to FFAs in vitro and in vivo.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 19 September 2007. DOI: 10.2337/db07-0075.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0075.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted August 20, 2007.
    • Received January 16, 2007.
| Table of Contents

This Article

  1. Diabetes vol. 56 no. 12 2927-2937
  1. Online-Only Appendix
  2. All Versions of this Article:
    1. db07-0075v1
    2. db07-0075v2
    3. 56/12/2927 most recent