title: Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia.
abstract: Nonobese diabetic (NOD) mice are a commonly used model of type 1 diabetes (T1D). However, not all animals will develop overt diabetes despite undergoing similar autoimmune insult. In this study, a comprehensive metabolomic approach, consisting of gas chromatography time-of-flight (GC-TOF) mass spectrometry (MS), ultra-high-performance liquid chromatography-accurate mass quadruple time-of-flight (UHPLC-qTOF) MS and targeted UHPLC-tandem mass spectrometry-based methodologies, was used to capture metabolic alterations in the metabolome and lipidome of plasma from NOD mice progressing or not progressing to T1D. Using this multi-platform approach, we identified >1,000 circulating lipids and metabolites in male and female progressor and nonprogressor animals (n = 71). Statistical and multivariate analyses were used to identify age- and sex-independent metabolic markers, which best differentiated metabolic profiles of progressors and nonprogressors. Key T1D-associated perturbations were related with 1) increases in oxidation products glucono-δ-lactone and galactonic acid and reductions in cysteine, methionine and threonic acid, suggesting increased oxidative stress; 2) reductions in circulating polyunsaturated fatty acids and lipid signaling mediators, most notably arachidonic acid (AA) and AA-derived eicosanoids, implying impaired states of systemic inflammation; 3) elevations in circulating triacylglyercides reflective of hypertriglyceridemia; and 4) reductions in major structural lipids, most notably lysophosphatidylcholines and phosphatidylcholines. Taken together, our results highlight the systemic perturbations that accompany a loss of glycemic control and development of overt T1D.
authors: National Institutes of Health West Coast Metabolomics Center, University of California Davis, Davis, California;
authors: Johannes
authors: J
authors: Fahrmann
authors: National Institutes of Health West Coast Metabolomics Center, University of California Davis, Davis, California;
authors: Dmitry
authors: D
authors: Grapov
authors: Department of Entomology and Cancer Center, University of California Davis, Davis, California; and.
authors: Jun
authors: J
authors: Yang
authors: Department of Entomology and Cancer Center, University of California Davis, Davis, California; and.
authors: Bruce
authors: B
authors: Hammock
authors: National Institutes of Health West Coast Metabolomics Center, University of California Davis, Davis, California;
authors: Oliver
authors: O
authors: Fiehn
authors: Department of Medicine, The University of Chicago, Chicago, Illinois.
authors: Graeme I
authors: GI
authors: Bell
authors: Department of Medicine, The University of Chicago, Chicago, Illinois mhara@midway.uchicago.edu.
authors: Manami
authors: M
authors: Hara
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D015228:Hypertriglyceridemia / Q000150:complications / Q000378:metabolism*; D007249:Inflammation / Q000150:complications / Q000378:metabolism*; D008297:Male; D055442:Metabolome; D051379:Mice; D016688:Mice, Inbred NOD; D018384:Oxidative Stress / Q000502:physiology*; D015854:Up-Regulation
keywords: diabetic mice; inflammation; metabolomics; oxidative stress