| Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet. | |
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MedLine Citation:
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PMID: 20415664 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The aim of the present study was to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, and pancreatic and hepatic remodelling in C57BL/6 mice fed on a very HF (high-fat) diet. Male C57BL/6 mice were fed on an HF (60% lipids) diet or SC (standard chow; 10% lipids) diet for 10 weeks, after which time the following drug treatments began: HF-T (HF diet treated with telmisartan; 5.2 mg x kg-1 of body weight x day-1), HF-S (HF diet treated with sitagliptin; 1.08 g x kg-1 of body weight.day-1), HF-M (HF diet treated with metformin; 310.0 mg x kg-1 of body weight x day-1), HF-TM (HF diet treated with telmisartan+metformin), HF-TS (HF diet treated with telmisartan+sitagliptin) and HF-SM (HF diet treated with sitagliptin+metformin). Treated groups also had free access to the HF diet, and treatments lasted for 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blot analysis and electron microscopy were used. The HF diet yielded an overweight phenotype, an increase in oral glucose intolerance, hyperinsulinaemia, hypertrophied islets and adipocytes, stage 2 steatosis (>33%), and reduced liver PPAR-alpha (peroxisome-proliferator-activated receptor-alpha) and GLUT-2 (glucose transporter-2) levels, concomitant with enhanced SREBP-1 (sterol-regulatory-element-binding protein-1) expression (P<0.0001). Conversely, all drug treatments resulted in significant weight loss, a reversal of insulin resistance, islet and adipocyte hypertrophy, and alleviated hepatic steatosis. Only the HF-T and HF-TS groups had body weights similar to the SC group at the end of the experiment, and the latter treatment reversed hepatic steatosis. Increased PPAR-alpha immunostaining in parallel with higher GLUT-2 and reduced SREBP-1 expression may explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-alpha (tumour necrosis factor-alpha) levels (P<0.0001) in the drug-treated groups. In conclusion, all of the drug treatments were effective in controlling the metabolic syndrome. The best results were achieved using telmisartan and sitagliptin as monotherapies or as a dual treatment, combining partial PPAR-gamma agonism and PPAR-alpha activation in the liver with extended incretin action. |
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Authors:
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Vanessa Souza-Mello; Bianca M Gregório; Fernando S Cardoso-de-Lemos; Laís de Carvalho; Márcia B Aguila; Carlos A Mandarim-de-Lacerda |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-06-08 |
Journal Detail:
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Title: Clinical science (London, England : 1979) Volume: 119 ISSN: 1470-8736 ISO Abbreviation: Clin. Sci. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-06-15 Completed Date: 2010-09-03 Revised Date: 2010-09-23 |
Medline Journal Info:
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Nlm Unique ID: 7905731 Medline TA: Clin Sci (Lond) Country: England |
Other Details:
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Languages: eng Pagination: 239-50 Citation Subset: IM |
Affiliation:
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Laboratory of Morphometry, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, 20551-030 Rio de Janeiro, RJ, Brazil. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Adipocytes
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pathology Angiotensin II Type 1 Receptor Blockers / therapeutic use Animals Benzimidazoles / therapeutic use* Benzoates / therapeutic use* Dietary Fats / administration & dosage* Dipeptidyl-Peptidase IV Inhibitors / therapeutic use Drug Evaluation, Preclinical / methods Drug Therapy, Combination Energy Intake / drug effects Glucose Tolerance Test Hypoglycemic Agents / therapeutic use Insulin Resistance Liver / physiopathology, ultrastructure Male Metabolic Syndrome X / drug therapy*, pathology, physiopathology Metformin / therapeutic use* Mice Mice, Inbred C57BL Obesity / drug therapy*, pathology, physiopathology Pancreas / physiopathology Pyrazines / therapeutic use* Triazoles / therapeutic use* |
| Chemical | |
Reg. No./Substance:
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0/Angiotensin II Type 1 Receptor Blockers; 0/Benzimidazoles; 0/Benzoates; 0/Dietary Fats; 0/Dipeptidyl-Peptidase IV Inhibitors; 0/Hypoglycemic Agents; 0/Pyrazines; 0/Triazoles; 0/sitagliptin; 144701-48-4/telmisartan; 657-24-9/Metformin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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