A metabolome-wide characterization of the diabetic phenotype in ZDF rats and its reversal by pioglitazone

Abstract

Type 2 diabetes (T2D) is a complex metabolic disease associated with alterations in glucose, lipid and protein metabolism. In order to characterize the biochemical phenotype of the Zucker diabetic fatty (ZDF) rat, the most common animal model for the study of T2D, and the impact of the insulin sensitizer pioglitazone, a global, mass spectrometry-based analysis of the metabolome was conducted. Overall, 420 metabolites in serum, 443 in the liver and 603 in the intestine were identified at study end. In comparison to two control groups, obese diabetic ZDF rats showed characteristic metabolic signatures that included hyperglycemia, elevated β-oxidation, dyslipidemia-featured by an increase in saturated and monounsaturated fatty acids and a decrease of medium chain and of polyunsaturated fatty acids in serum-and decreased amino acid levels, consistent with their utilization in hepatic gluconeogenesis. A 13-week treatment with the PPARγ agonist pioglitazone reversed most of these signatures: Pioglitazone improved glycemic control and the fatty acid profile, elevated amino acid levels in the liver, but decreased branched chain amino acids in serum. The hitherto most comprehensive metabolic profiling study identified a biochemical blueprint for the ZDF diabetic model and captured the impact of genetic, nutritional and pharmacological perturbations. The in-depth characterization on the molecular level deepens the understanding and further validates the ZDF rat as a suitable preclinical model of diabetes in humans.

Fig 1

Relative levels and concentration ratios of glucose (upper panel) and 1,5-anhydroglucitol (lower panel) in serum, liver and intestine. The fold change for the matrices indicated is presented in the excerpt from the heat map table (green: indicates significant difference (p≤0.05) between the groups shown; red: indicates significant difference (p≤0.05) between the groups shown).

Fig 2. Relative levels and concentration ratios of saccharides in the intestine (red: Indicates significant difference (p≤0.05) between the groups shown).

Fig 3. Relative levels and concentration ratios of the triacylglyceride degradation product glycerol, the fatty acid β-oxidation product 3-hydroxybutyrate, and cholesterol in serum (red: Indicates significant difference (p≤0.05) between the groups shown).

Fig 4. Relative levels and concentration ratios of oxidized glutathione, cysteine-glutathione and ophthalmate in serum (green: Indicates significant difference (p≤0.05) between the groups shown; red: Indicates significant difference (p≤0.05) between the groups shown).

Fig 5. Relative levels and concentration ratios of glucose and 1,5-anhydroglucitol in serum, intestine and liver (green: Indicates significant difference (p≤0.05) between the groups shown; red: Indicates significant difference (p≤0.05) between the groups shown).