Chronic palmitic acid-induced lipotoxicity correlates with defective trafficking of ATP sensitive potassium channels in pancreatic β cells.

Abstract Lipotoxicity is associated with a high level of fatty acid accumulation in pancreatic β-cells. An overload of free fatty acids contributes to pancreatic β-cell apoptosis and dysfunction. Insulin secretion involves sequential ionic events upon glucose stimulation. ATP sensitive potassium (K ATP ) channels serve as glucose sensors and effectively initiate glucose-stimulated insulin secretion. This study investigated the effects of lipotoxicity on the trafficking of K ATP channels in pancreatic β cells using chronic palmitic acid –injected mice and treated insulinoma cells. The chronic palmitic acid -injected mice displayed type II diabetic characteristics. The pancreatic sections of these mice exhibited a decrease in the expression of K ATP channels. We then tested the time and dose effects of palmitic acid on the cell viability of INS-1 cells. We observed a significant decrease in the surface expression of K ATP channels after 72 h of treatment with 0.4 mM palmitic acid. In addition, this treatment induced pancreatic β-cell apoptosis by increasing cleaved caspase 3 protein level. Our results demonstrated cotreatment with glibenclamide, the sulfonylurea compounds for type II diabetes mellitus, in palmitic acid -treated cells reduces cell death and recovers the glucose stimulated insulin secretion through increasing the surface expression of K ATP channels. Importantly, glibenclamide also improved glucose tolerance, triglyceride concentration, and insulin sensitivity in the palmitic acid-injected mice. In conclusion, an increase in the surface expression of K ATP channels restores insulin secretion, reduces pancreatic β-cell’s apoptosis, highlighting correct trafficking of K ATP channels is important in survival of β-cells during lipotoxicity.