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: Johannes Fahrmann, Dmitry Grapov, Jun Yang, Bruce Hammock, Oliver Fiehn, Graeme I Bell, Manami Hara
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 308 Issue 11 Pg. E978-89 (Jun 01 2015) ISSN: 1522-1555 [Electronic] United States
• PMID: 25852003 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Topics

• Animals
• Diabetes Mellitus, Experimental (complications, metabolism)
• Diabetes Mellitus, Type 1 (metabolism, pathology)
• Down-Regulation
• Female
• Hypertriglyceridemia (complications, metabolism)
• Inflammation (complications, metabolism)
• Male
• Metabolome
• Mice
• Mice, Inbred NOD
• Oxidative Stress (physiology)
• Up-Regulation