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

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 HgCl 2 or methylmercury triggered reactive oxygen species (ROS) production and decreased insulin secretion in ␤-cell-derived HIT-T15 cells and isolated 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 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 ␤-cell dysfunction.

Heavy metals, islet function and diabetes development

“…84,109 Our recent study has also shown that mercury is capable of affecting the islet β-cell function and survival through an oxidative stress pathway in vivo and in vitro. 104,110 Low-dose mercury induced mouse pancreatic islet β-cell dysfunction through a PI3K-activated or oxidative stress-triggered Akt pathway in cell culture and animal models. 110 Moreover, methylmercury could induce oxidative stress-triggered β-cell apoptosis and death.…”

“…104,110 Low-dose mercury induced mouse pancreatic islet β-cell dysfunction through a PI3K-activated or oxidative stress-triggered Akt pathway in cell culture and animal models. 110 Moreover, methylmercury could induce oxidative stress-triggered β-cell apoptosis and death. 104 Thus, these observations provide evidences to confirm the possibility that mercury is an environmental risk factor for diabetes.…”

Inhibition of Aldehyde Dehydrogenase 2 by Oxidative Stress Is Associated with Cardiac Dysfunction in Diabetic Rats

“…Intracellular ROS levels were monitored by flow cytometry by use of a peroxide-sensitive fluorescent probe, 2',7'-dichlorofluorescin diacetate (DCFH-DA) (Sigma) (25). Heart tissue was dissected and immediately frozen in liquid nitrogen.…”

The Effect of Mercury Vapor and the Role of Green Tea Extract on Brain Cells

“…[1][2][3][4][5][6][7][8] Merkuri (Hg) sudah lama digunakan secara luas di bidang kedokteran gigi sebagai bahan restorasi, yaitu sebagai campuran pada tambalan amalgam. 3 Pasien maupun personil kesehatan gigi sangat beresiko terhadap keracunan merkuri, tetapi personil kesehatan gigi lebih beresiko karena mereka bisa terpapar secara terus-menerus.…”

“…Konsentrasi submikromolar dari HgCl 2 atau metilmerkuri memicu produksi ROS. 5 Merkuri dapat masuk ke dalam sel dan merusak sel. Merkuri dapat mengurangi produksi glutation (GSH) dan menghambat aktivitas enzim glutation peroksidase (GPx) dan menimbulkan stres oksidatif pada otak dan organ tubuh lainnya.…”