The Role of Phosphoinositide 3-Kinase/Akt Signaling in Low-Dose Mercury- Induced Mouse Pancreatic Beta-Cell Dysfunction in Vitro and in Vivo
Resource
DIABETES v.55 n.6 pp.1614-1624
Journal
DIABETES
Journal Volume
v.55
Journal Issue
n.6
Pages
1614-1624
Date Issued
2006
Date
2006
Author(s)
CHEN, YA-WEN
HUANG, CHUN-FA
TSAI, KEH- SUNG
YANG, RONG-SEN
YEN, CHENG-CHIEH
YANG, CHING-YAO
LIN-SHIAU, SHOEI-YN
LIU, SHING-HWA
Abstract
The relationship between oxidation stress and phosphoinositide 3-kinase ( PI3K) signaling in pancreatic 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 mouse islets. Mercury increased PI3K activity and its downstream effector Akt phosphorylation. Antioxidant Nacetyl-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 p 85 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 dysfunction. Diabetes 55:1614–1624, 2006
Subjects
AKT/PROTEIN KINASE-B
OXIDATIVE STRESS
INSULIN-SECRETION
PHOSPHATIDYLINOSITOL 3-KINASE
LIPID-PEROXIDATION
MINAMATA DISEASE
SDGs