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), 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.

Obesity and Cancer: Existing and New Hypotheses for a Causal Connection

“…The increased tryptophan oxidation correlated with abdominal adiposity rather than overall BMI, suggesting that it specifically involved an aspect of fat metabolism – the basis of the metabolic syndrome. The inflammation-induced activation of IDO and its metabolism of tryptophan to kynurenine has been proposed as the major mechanism linking inflammation, depression, type-1 diabetes and obesity ( Engin and Engin, 2017 ; Murfitt et al, 2017 ; Zhong et al, 2017 ), partly attributable to the effects of tryptophan metabolites on food craving ( Dalkner et al, 2017 ).…”

Synthesis of cinnabarinic acid by metabolically engineered Pseudomonas chlororaphis GP72

“…As shown in Figure (pathway A), CA is the byproduct of tryptophan degradation in animals (including human) and some fungi, such as P. cinnabarinus (Eggert et al, ; Fazio et al, ). Because this pathway is primarily used for the biosynthesis of quinolinic acid and NAD, the accumulation of CA is typically low in these organisms (Murfitt et al, ). Compared with eukaryotes, prokaryotes possess the advantages of rapid reproduction and easy genetic modification.…”

“…P. cinnabarinus and animals typically produce CA, which is formed by the polymerization of two molecules of HAA (Eggert et al, ; Fazio et al, ). HAA derived from tryptophan catabolism is primarily used for the biosynthesis of quinolinic acid and NAD (Murfitt et al, ). Thus, it is difficult for HAA and CA to accumulate in these hosts.…”

Evaluation of the antitumor effects of PP242 in a colon cancer xenograft mouse model using comprehensive metabolomics and lipidomics

“…Metabolomics, the comprehensive study of small molecule metabolites, appears to be a robust tool to assess diverse biological samples, including cells, biofluids and tissues, in response to biological stimuli, such as disease and drugs 16 , 17 . Lipidomics, which is a subset of metabolomics, mainly contributes in the evaluation of various lipid species in complex biological samples 18 . Combined metabolomics and lipidomics approaches have been widely applied and used to assess the pathophysiological pathways related to disease progression, identify biomarkers and monitor the underlying mechanism of drug effects and toxicity 19 .…”