Metabolomics and Lipidomics Study of Mouse Models of Type 1 Diabetes Highlights Divergent Metabolism in Purine and Tryptophan Metabolism Prior to Disease Onset.

Abstract

With the increase in incidence of type 1 diabetes (T1DM), particularly in Westernised societies, 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 overt disease. In this study we have applied a liquid chromatography (LC-) and gas chromatography (GC-) mass spectrometry (MS) metabolomics and lipidomics analysis of blood plasma and pancreas tissue extracts to follow the progression of disease in three models related to autoimmune diabetes: the non-obese diabetic (NOD) mouse, which is 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. Comparing between the NOD and NOD-E mice we show the development of T1DM in the NOD mouse 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.