RGD Reference Report - Nonobese diabetic (NOD) mice congenic for a targeted deletion of 12/15-lipoxygenase are protected from autoimmune diabetes. - Rat Genome Database

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

Authors: McDuffie, M  Maybee, NA  Keller, SR  Stevens, BK  Garmey, JC  Morris, MA  Kropf, E  Rival, C  Ma, K  Carter, JD  Tersey, SA  Nunemaker, CS  Nadler, JL 
Citation: McDuffie M, etal., Diabetes. 2008 Jan;57(1):199-208. Epub 2007 Oct 16.
RGD ID: 5509611
Pubmed: PMID:17940120   (View Abstract at PubMed)
PMCID: PMC2993320   (View Article at PubMed Central)
DOI: DOI:10.2337/db07-0830   (Journal Full-text)

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 beta-cells. It enhances interleukin 12 production by macrophages, and several of its products induce apoptosis of beta-cells at nanomolar concentrations in vitro. We had previously demonstrated a role for 12/15-LO in beta-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 beta-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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
type 1 diabetes mellitus  ISOAlox15 (Mus musculus)5509611; 5509611 RGD 
type 1 diabetes mellitus  IMP 5509611 RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View

RGD Manual Annotations

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
type 1 diabetes mellitus pathway  ISOAlox15 (Mus musculus)5509611; 5509611 RGD 
type 1 diabetes mellitus pathway  IMP 5509611 RGD 
Objects Annotated

Genes (Rattus norvegicus)
Alox15  (arachidonate 15-lipoxygenase)

Genes (Mus musculus)
Alox15  (arachidonate 15-lipoxygenase)

Genes (Homo sapiens)
ALOX15  (arachidonate 15-lipoxygenase)


Additional Information