Abstract

OBJECTIVE— 12/15-lipoxygenase (12/15-LO), one of a family of fatty acid oxidoreductase enzymes, reacts with polyenoic fatty acids to produce proinflammatory lipids. 12/15-LO is expressed in macrophages and pancreatic β-cells. It enhances interleukin 12 production by macrophages, and several of its products induce apoptosis of β-cells at nanomolar concentrations in vitro. We had previously demonstrated a role for 12/15-LO in β-cell damage in the streptozotocin model of diabetes. Since the gene encoding 12/15-LO (gene designation Alox15) lies within the Idd4 diabetes susceptibility interval in NOD mice, we hypothesized that 12/15-LO is also a key regulator of diabetes susceptibility in the NOD mouse.

RESEARCH DESIGN AND METHODS— We developed NOD mice carrying an inactivated 12/15-LO locus (NOD-Alox15^null) using a “speed congenic” protocol, and the mice were monitored for development of insulitis and diabetes.

RESULTS— NOD mice deficient in 12/15-LO develop diabetes at a markedly reduced rate compared with NOD mice (2.5 vs. >60% in females by 30 weeks). Nondiabetic female NOD-Alox15^null mice demonstrate improved glucose tolerance, as well as significantly reduced severity of insulitis and improved β-cell mass, when compared with age-matched nondiabetic NOD females. Disease resistance is associated with decreased numbers of islet-infiltrating activated macrophages at 4 weeks of age in NOD-Alox15^null mice, preceding the development of insulitis. Subsequently, islet-associated infiltrates are characterized by decreased numbers of CD4⁺ T cells and increased Foxp3⁺ cells.

CONCLUSIONS— These results suggest an important role for 12/15-LO in conferring susceptibility to autoimmune diabetes in NOD mice through its effects on macrophage recruitment or activation.