The Role of Phosphoinositide 3-Kinase/Akt Signaling in Low-Dose Mercury–Induced Mouse Pancreatic β-Cell Dysfunction In Vitro and In Vivo

  1. Ya Wen Chen1,
  2. Chun Fa Huang1,
  3. Keh Sung Tsai2,
  4. Rong Sen Yang3,
  5. Cheng Chieh Yen14,
  6. Ching Yao Yang156,
  7. Shoei Yn Lin-Shiau1 and
  8. Shing Hwa Liu167
  1. 1Institute of Toxicology, National Taiwan University, Taipei, Taiwan
  2. 2Department of Laboratory Medicine, National Taiwan University, Taipei, Taiwan
  3. 3Department of Orthopaedics, College of Medicine, National Taiwan University, Taipei, Taiwan
  4. 4Department of Occupational Safety and Health, College of Health Care and Management, Chung San Medical University, Taichung, Taiwan
  5. 5Department of Traumatology, National Taiwan University, Taipei, Taiwan
  6. 6Department of Surgery, National Taiwan University, Taipei, Taiwan
  7. 7Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan
  1. Address correspondence and reprint requests to Shing-Hwa Liu, PhD, Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 10043, Taiwan. E-mail: shliu{at}


The relationship between oxidation stress and phosphoinositide 3-kinase (PI3K) signaling in pancreatic β-cell dysfunction remains unclear. Mercury is a well-known toxic metal that induces oxidative stress. Submicromolar-concentration HgCl2 or methylmercury triggered reactive oxygen species (ROS) production and decreased insulin secretion in β-cell–derived HIT-T15 cells and isolated mouse islets. Mercury increased PI3K activity and its downstream effector Akt phosphorylation. Antioxidant N-acetyl-l-cysteine (NAC) prevented mercury-induced insulin secretion inhibition and Akt phosphorylation but not increased PI3K activity. Inhibition of PI3K/Akt activity with PI3K inhibitor or by expressing the dominant-negative p85 or Akt prevented mercury-induced insulin secretion inhibition but not ROS production. These results indicate that both PI3K and ROS independently regulated Akt signaling–related, mercury-induced insulin secretion inhibition. We next observed that 2- or 4-week oral exposure to low-dose mercury to mice significantly caused the decrease in plasma insulin and displayed the elevation of blood glucose and plasma lipid peroxidation and glucose intolerance. Akt phosphorylation was shown in islets isolated from mercury-exposed mice. NAC effectively antagonized mercury-induced responses. Mercury-induced in vivo effects and increased blood mercury were reversed after mercury exposure was terminated. These results demonstrate that low-dose mercury–induced oxidative stress and PI3K activation cause Akt signaling–related pancreatic β-cell dysfunction.


  • Y.W.C., C.F.H., K.S.T., and R.S.Y. contributed equally to this work.

    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 March 20, 2006.
    • Received January 6, 2006.
| Table of Contents