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Nonobese Diabetic (NOD) Mice Congenic for a Targeted Deletion of 12/15-Lipoxygenase Are Protected From Autoimmune Diabetes

From the University of Virginia, Charlottesville, Virginia

Address correspondence and reprint requests to Jerry L. Nadler, MD, University of Virginia, P.O. Box 801405, Charlottesville, VA 22908

Key Words: EAE, experimental allergic encephalomyelitis • HETE, hydroxyeicosatetranoic acid • IL, interleukin

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.

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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]