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

Johannes Fahrmann, Dmitry Grapov, Jun Yang, Bruce Hammock, Oliver Fiehn, Graeme I. Bell, Manami Hara

Research output: Contribution to journalArticle

24 Citations (Scopus)

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-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.

Original languageEnglish (US)
Pages (from-to)E978-E989
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume308
Issue number11
DOIs
StatePublished - Jun 1 2015

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Inbred NOD Mouse
Metabolome
Type 1 Diabetes Mellitus
Oxidative Stress
Inflammation
Lipids
Mass Spectrometry
Lysophosphatidylcholines
Metabolomics
Eicosanoids
Hypertriglyceridemia
Lactones
Tandem Mass Spectrometry
Phosphatidylcholines
Unsaturated Fatty Acids
Arachidonic Acid
Liquid Chromatography
Methionine
Gas Chromatography
Cysteine

Keywords

  • Diabetic mice
  • Inflammation
  • Metabolomics
  • Oxidative stress

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Endocrinology, Diabetes and Metabolism

Cite this

Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia. / Fahrmann, Johannes; Grapov, Dmitry; Yang, Jun; Hammock, Bruce; Fiehn, Oliver; Bell, Graeme I.; Hara, Manami.

In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 308, No. 11, 01.06.2015, p. E978-E989.

Research output: Contribution to journalArticle

Fahrmann, Johannes ; Grapov, Dmitry ; Yang, Jun ; Hammock, Bruce ; Fiehn, Oliver ; Bell, Graeme I. ; Hara, Manami. / Systemic alterations in the metabolome of diabetic NOD mice delineate increased oxidative stress accompanied by reduced inflammation and hypertriglyceremia. In: American Journal of Physiology - Endocrinology and Metabolism. 2015 ; Vol. 308, No. 11. pp. E978-E989.
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