Journal
DIABETES
Volume 57, Issue 1, Pages 199-208Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db07-0830
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Funding
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK051112, T32DK007320, P30DK063609, R01DK055240] Funding Source: NIH RePORTER
- NIDDK NIH HHS [R01 DK055240, R01 DK55240, R01 DK051112-03, DK063609, T32 DK007320, P30 DK063609, DK007320-29] Funding Source: Medline
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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 P-cells. It enhances interleukin 12 production by macrophages, and several of its products induce apoptosis of P-cells at nanomolar concentrations in vitro. We had previously demonstrated a role for 12/15-LO in P-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 P-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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