Evidence for a Role of Superoxide Generation in Glucose-Induced β-Cell Dysfunction In Vivo

  1. Christine Tang1,
  2. Ping Han1,
  3. Andrei I. Oprescu2,
  4. Simon C. Lee1,
  5. Armen V. Gyulkhandanyan1,
  6. Gary N.Y. Chan1,
  7. Michael B. Wheeler1 and
  8. Adria Giacca1,2,3
  1. 1Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  2. 2Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  3. 3Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  1. Address correspondence and reprint requests to Adria Giacca, 1 King's College Circle, Medical Sciences Building, Room 3336, Toronto ON, Canada. E-mail: adria.giacca{at}


OBJECTIVE— Prolonged elevation of glucose can adversely affect β-cell function. In vitro studies have linked glucose-induced β-cell dysfunction to oxidative stress; however, whether oxidative stress plays a role in vivo is unclear. Therefore, our objective was to investigate the role of oxidative stress in an in vivo model of glucose-induced β-cell dysfunction.

RESEARCH DESIGN AND METHODS— Wistar rats were infused intravenously with glucose for 48 h to achieve 20 mmol/l hyperglycemia with/without co-infusion of one of the following antioxidants: taurine (2-amino ethanesulfonic acid) (TAU), an aldehyde scavenger; N-acetylcysteine (NAC), a precursor of glutathione; or tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) (TPO), a superoxide dismutase mimetic. This was followed by islet isolation or hyperglycemic clamp.

RESULTS— A 48-h glucose infusion decreased glucose-stimulated insulin secretion (GSIS) and elevated reactive oxygen species (ROS), total superoxide, and mitochondrial superoxide in freshly isolated islets. TPO prevented the increase in total and mitochondrial superoxide and the β-cell dysfunction induced by high glucose. However, TAU and NAC, despite completely normalizing H2DCF-DA (dihydro-dichlorofluorescein diacetate)-measured ROS, did not prevent the increase in superoxide and the decrease in β-cell function induced by high glucose. TPO but not TAU also prevented β-cell dysfunction induced by less extreme hyperglycemia (15 mmol/l) for a longer period of time (96 h). To further investigate whether TPO is effective in vivo, a hyperglycemic clamp was performed. Similar to the findings in isolated islets, prolonged glucose elevation (20 mmol/l for 48 h) decreased β-cell function as assessed by the disposition index (insulin secretion adjusted for insulin sensitivity), and co-infusion of TPO with glucose completely restored β-cell function.

CONCLUSIONS— These findings implicate superoxide generation in β-cell dysfunction induced by prolonged hyperglycemia.


  • Published ahead of print at on 6 August 2007. DOI: 10.2337/db07-0279.

    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.

    • Received February 27, 2007.
    • Accepted July 28, 2007.
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  1. Diabetes vol. 56 no. 11 2722-2731
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