Abstract
BackgroundThe 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.MethodsHere 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.ResultsMultiple 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.ConclusionsMetabolomic 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.
Highlights
The prevalence, and associated healthcare burden, of diabetes mellitus is increasing worldwide
The hyperglycemia is caused as a consequence of a deficiency in insulin in type 1 diabetes (T1D), and is a feature of late type 2 diabetes (T2D) along with insulin resistance
Treatment of the rats with intraperitoneal STZ resulted in elevated plasma glucose levels consistent with diabetes (>30 mmol/L), whereas non-treated rats without STZ injection had normal glucose levels (
Summary
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. Diabetes mellitus (DM) is a chronic debilitating condition that is rapidly increasing in prevalence worldwide, as a consequence of increases in obesity, changing patterns of diet and physical activity, and ageing populations. Molecular pathophysiological mechanisms that precede hyperglycemia, or are observed with the clinical symptoms of DM, include, among others, alterations in lipid and amino acid metabolism [3,4,5], changes in hormone levels (including insulin [6] and adiponectin [7]), increases in adipokine levels [8] and alterations in copper metabolism [9]. Current interventions in DM are aimed at controlling blood glucose levels, dyslipidemia and blood pressure, but these have only modest effects on reducing risk of progression to complications, so better treatments are urgently required
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