With the increase in incidence of type 1 diabetes (T1DM), there is an urgent need to understand the early molecular and metabolic alterations that accompany the autoimmune disease. This is not least because in murine models early intervention can prevent the development of disease. We have applied a liquid chromatography (LC-) and gas chromatography (GC-) mass spectrometry (MS) metabolomics and lipidomics analysis of blood plasma and pancreas tissue to follow the progression of disease in three models related to autoimmune diabetes: the nonobese diabetic (NOD) mouse, susceptible to the development of autoimmune diabetes, and the NOD-E (transgenic NOD mice that express the I-E heterodimer of the major histocompatibility complex II) and NOD-severe combined immunodeficiency (SCID) mouse strains, two models protected from the development of diabetes. All three analyses highlighted the metabolic differences between the NOD-SCID mouse and the other two strains, regardless of diabetic status indicating that NOD-SCID mice are poor controls for metabolic changes in NOD mice. By comparing NOD and NOD-E mice, we show the development of T1DM in NOD mice is associated with changes in lipid, purine, and tryptophan metabolism, including an increase in kynurenic acid and a decrease in lysophospholipids, metabolites previously associated with inflammation.
The authors thank Dr. Michael Eidan for the expert technical assistance in processing the lipidomic data. This work was funded by a Medical Research Council Project grant (G0801841) and the Medical Research Council Lipid Programming and Signaling program grant (MC_UP_A090_1006).
Data Availability StatementThe Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jproteome.7b00489.
All data are available through the MetaboLights repository (http://www.ebi.ac.uk/metabolights/).
- Chromatography, Liquid
- Diabetes Mellitus, Type 1/immunology
- Discriminant Analysis
- Disease Models, Animal
- Gas Chromatography-Mass Spectrometry
- Gene Expression
- Histocompatibility Antigens Class II/genetics
- Islets of Langerhans/immunology
- Kynurenic Acid/metabolism
- Lipid Metabolism
- Mice, Inbred NOD
- Mice, SCID
- Mice, Transgenic
- Prediabetic State/immunology
- Principal Component Analysis
- Protein Multimerization
- nonobese diabetic (NOD) mouse
- NOD-severe combined immunodeficiency (SCID) mouse
- mass spectrometry
- kynurenic acid