On the biochemical and molecular mechanisms by which malathion induces dysfunction in pancreatic islets in vivo and in vitro

• Pancreatic endocrine system is affected in acute poisoning with malathion.
• Malathion impairs glucose metabolism by increasing oxidative stress markers.
• Impairment of glucose metabolism is critical in dysfunction of insulin induced by malathion.

Recent studies showed that organophosphorus pesticides can increase incidence of metabolic disorders and diabetes. Considering the importance of pancreas in regulating blood glucose, the effect of malathion on essential elements of glucose-stimulated insulin secretion (GSIS) in in vitro and in vivo conditions were evaluated.After dividing of rats into control and treatment groups, oral glucose tolerance test (OGTT) was examined and then kinetic of glucose as well as pancreatic response to raise blood glucose were evaluated. After isolation of islets from pancreas, its function as well as oxidative stress markers and essential elements of GSIS were examined.Malathion at dose of 400 mg/kg impaired GTT and increased AUC0–180 min (P = 0.047) and T1/2β of glucose (P = 0.0016), and reduced insulin response (P = 0.005) 30 min after oral administering of glucose. In addition to impaired glucose tolerance, there were significant increases in lipid peroxidation (P < 0.001), carbonyl groups (P = 0.007) and 8-deoxyguanosine (P = 0.011) as the biomarkers of reactive oxygen species (ROS)-mediated damage to lipid, protein and DNA, respectively in islets. In static condition, a remarkable decrease was observed in ratio of insulin release/mM glucose (P < 0.001) and a dramatic increase was seen in ROS formation at all glucose levels. Malathion only reduced ATP/ADP ratio in stimulating concentrations of glucose. Despite the dramatic reduction of glucokinase (GCK) mRNA expression (P = 0.004), the expression of glucose transporter 2 (GLUT2) (P = 0.01) was increased significantly.ConclusionDysfunction of glucose metabolism and impairment of insulin secretion are associated with a depletion of energy and induction of oxidative stress following acute exposure to malathion.

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