Platelet-type 12-lipoxygenase deletion provokes a compensatory 12/15-lipoxygenase increase that exacerbates oxidative stress in mouse islet β cells.

In type 1 diabetes, an autoimmune event increases oxidative stress in islet β cells, giving rise to cellular dysfunction and apoptosis. Lipoxygenases are enzymes that catalyze the oxygenation of polyunsaturated fatty acids that can form lipid metabolites involved in several biological functions, including oxidative stress. 12-Lipoxygenase and 12/15-lipoxygenase are related but distinct enzymes that are expressed in pancreatic islets, but their relative contributions to oxidative stress in these regions are still being elucidated. In this study, we used mice with global genetic deletion of the genes encoding 12-lipoxygenase ( []) or 12/15-lipoxygenase () to compare the influence of each gene deletion on β cell function and survival in response to the β cell toxin streptozotocin. mice exhibited greater impairment in glucose tolerance following streptozotocin exposure than WT mice, whereas mice were protected against dysglycemia. These changes were accompanied by evidence of islet oxidative stress in mice and reduced oxidative stress in mice, consistent with alterations in the expression of the antioxidant response enzymes in islets from these mice. Additionally, islets from mice displayed a compensatory increase in gene expression, and treatment of these mice with the 12/15-lipoxygenase inhibitor ML-351 rescued the dysglycemic phenotype. Collectively, these results indicate that loss activates a compensatory increase in that sensitizes mouse β cells to oxidative stress.