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.
Highlights
The number of people suffering from type 2 diabetes (T2D) and its complications has risen significantly in the past decades in all continents of the globe, rendering the disease a major threat for public health.[1,2] Type 2 diabetes is a slowly progressing, multifactorial disease defined by hyperglycemia that exhibits multiple alterations in glucose, lipid and protein metabolism
Blood glucose levels were almost unchanged in the Fa/? and obese fa/fa group receiving normal chow (5.91 mM vs. 6.53 mM), but fa/fa animals under high fat diet developed hyperglycemia, as indicated by blood glucose levels of 19.7 mM
The treatment of fa/fa animals under high fat diet with pioglitazone led to a pronounced decrease of blood glucose levels to 6.37 mM
Summary
The number of people suffering from type 2 diabetes (T2D) and its complications has risen significantly in the past decades in all continents of the globe, rendering the disease a major threat for public health.[1,2] Type 2 diabetes is a slowly progressing, multifactorial disease defined by hyperglycemia that exhibits multiple alterations in glucose, lipid and protein metabolism. The specific roles of all authors are articulated in the ‘author contributions’ section
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