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Non-obese diabetic (NOD) mice congenic for a targeted deletion of 12/15- lipoxygenase are protected from autoimmune diabetes.

University of Virginia

Objective: 12/15-lipoxygenase (12/15-LO), one of a family of fatty acid oxidoreductase enzymes, reacts with polyenoic fatty acids to produce pro-inflammatory lipids. 12/15-LO is expressed in macrophages and pancreatic ß-cells. It enhances interleukin 12 production by macrophages, and several of its products induce apoptosis of ß cells at nanomolar concentrations in vitro. We had previously demonstrated a role for 12/15-LO in ß-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 to NOD mice (2.5% vs. >60% in females by 30 weeks). Non-diabetic female NOD-Alox15^null mice demonstrate improved glucose tolerance, as well as significantly reduced severity of insulitis and improved ß-cell mass, when compared to age-matched non-diabetic 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.

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				S. P. Weisberg and R. L. Leibel An Apparent Role for Alox15 in the Pathogenesis of Diabetes in the NOD Mouse: Parsing the Supporting Genetic Data Diabetes, January 1, 2008; 57(1): 1 - 2. [Full Text] [PDF]