Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia

Abstract

Hara M. Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia. Am J Physiol Endocrinol Metab 308: E978-E989, 2015. First published April 8, 2015; doi:10.1152/ajpendo.00019.2015.-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-highperformance liquid chromatography-accurate mass quadruple time-offlight (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 Ͼ1,000 circulating lipids and metabolites in male and female progressor and nonprogressor animals (n ϭ 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-␦-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 AAderived 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. diabetic mice; metabolomics; inflammation; oxidative stress TYPE 1 DIABETES (T1D) is an autoimmune disease characterized by the selective destruction of pancreatic ␤-cells. Currently, it is considered that the autoimmune insult is the primary driver of ␤-cell destruction that leads to development of T1D. However, it is becoming increasingly evident that early metabolic perturbations are inherently involved in the development and progression of T1D (39,40,53). These metabolic alterations may potentiate or attenuate ␤-cell loss and dysfunction. Oresic et al. (40) reported that alterations in branched-chain amino acids (BCAA) and lipid metabolism preceded the appearance of autoantibodies in children who later progressed to T1D. Pflueger et al. (44) found that, independent of age-related differences, autoantibody-positive children had higher levels of odd-chain triglycerides and polyunsaturated fatty acid (PUFA)-containing phospholipids than autoantibody-negative children. Furthermore, it was found that children who developed autoantibodies by age 2 yr had a signific...

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