Research Article Details
| Article ID: | A52166 |
| PMID: | 30481177 |
| Source: | PLoS One |
| Title: | 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. |
| DOI: | 10.1371/journal.pone.0207210 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| S04 | Anti-oxidative stress | oxidative stress | α-tocopherol: antioxidant | Vitamin E | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name |
|---|
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I13 | 3146 | Lipid metabolism disorder | An inherited metabolic disorder that involves the creation and degradation of lipids. http://en.wikipedia.org/wiki/Lipid_metabolism | disease of metabolism/ inherited metabolic disorder | Details |
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D328 | Serine | Chemical drug | DB00133 | SRR | Improve insulin resistance | Under clinical trials | Details |
| D504 | Polyunsaturated Fatty Acids | Supplement | -- | -- | -- | Under clinical trials | Details |
| D275 | Pioglitazone | Chemical drug | DB01132 | PPARG agonist | Improve insulin resistance | Advanced in clinical trials | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |