TY - JOUR
T1 - Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia
AU - Fahrmann, Johannes
AU - Grapov, Dmitry
AU - Yang, Jun
AU - Hammock, Bruce
AU - Fiehn, Oliver
AU - Bell, Graeme I.
AU - Hara, Manami
N1 - Publisher Copyright:
© 2015 the American Physiological Society.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - 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 >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 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.
AB - 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 >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 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.
KW - Diabetic mice
KW - Inflammation
KW - Metabolomics
KW - Oxidative stress
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U2 - 10.1152/ajpendo.00019.2015
DO - 10.1152/ajpendo.00019.2015
M3 - Article
C2 - 25852003
AN - SCOPUS:84930855003
SN - 0193-1849
VL - 308
SP - E978-E989
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 11
ER -