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Metabolomic analysis of rat serum in streptozotocin-induced diabetes and after treatment with oral triethylenetetramine (TETA)

Marta Ugarte1*, Marie Brown12, Katherine A Hollywood12, Garth J Cooper1234, Paul N Bishop12 and Warwick B Dunn125*

Author Affiliations

1 School of Biomedicine and Manchester NIHR Biomedical Research Centre, AV Hill Building, The University of Manchester, Oxford Road, Manchester, M13 9PL, UK

2 Centre for Advanced Discovery and Experimental Therapeutics, School of Biomedicine, University of Manchester and Manchester Academic Health Sciences Centre, Central Manchester NHS Foundation Trust, York Place, Oxford Road, Manchester, M13 9WL, UK

3 Maurice Wilkins Centre for Molecular Biodiscovery, School of Biological Sciences, Thomas Building, The University of Auckland, Private Bag 92019, Auckland Mail Centre, Auckland 1142, New Zealand

4 Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK

5 Manchester Centre for Integrative Systems Biology and School of Chemistry, Manchester Interdisciplinary Biocentre, University of Manchester, 131 Princess Street, Manchester, M1 7DN, UK

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Genome Medicine 2012, 4:35  doi:10.1186/gm334

Published: 30 April 2012



The prevalence, and associated healthcare burden, of diabetes mellitus is increasing worldwide. Mortality and morbidity are associated with diabetic complications in multiple organs and tissues, including the eye, kidney and cardiovascular system, and new therapeutics to treat these complications are required urgently. Triethylenetetramine (TETA) is one such experimental therapeutic that acts to chelate excess copper (II) in diabetic tissues and reduce oxidative stress and cellular damage.


Here we have performed two independent metabolomic studies of serum to assess the suitability of the streptozotocin (STZ)-induced rat model for studying diabetes and to define metabolite-related changes associated with TETA treatment. Ultraperformance liquid chromatography-mass spectrometry studies of serum from non-diabetic/untreated, non-diabetic/TETA-treated, STZ-induced diabetic/untreated and STZ-induced diabetic/TETA-treated rats were performed followed by univariate and multivariate analysis of data.


Multiple metabolic changes related to STZ-induced diabetes, some of which have been reported previously in other animal and human studies, were observed, including changes in amino acid, fatty acid, glycerophospholipid and bile acid metabolism. Correlation analysis suggested that treatment with TETA led to a reversal of diabetes-associated changes in bile acid, fatty acid, steroid, sphingolipid and glycerophospholipid metabolism and proteolysis.


Metabolomic studies have shown that the STZ-induced rat model of diabetes is an appropriate model system to undertake research into diabetes and potential therapies as several metabolic changes observed in humans and other animal models were also observed in this study. Metabolomics has also identified several biological processes and metabolic pathways implicated in diabetic complications and reversed following treatment with the experimental therapeutic TETA.