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A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications in a rat model of type 2 diabetes.
- Source :
-
Diabetologia [Diabetologia] 2018 Oct; Vol. 61 (10), pp. 2235-2246. Date of Electronic Publication: 2018 Jul 21. - Publication Year :
- 2018
-
Abstract
- Aims/hypothesis: The metabolic syndrome is a cluster of risk correlates that can progress to type 2 diabetes. The present study aims to evaluate a novel molecule with a dual action against the metabolic syndrome and type 2 diabetes.<br />Methods: We developed and tested a novel dual modulator, RB394, which acts as a soluble epoxide hydrolase (sEH) inhibitor and a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist in rat models of the metabolic syndrome-the obese spontaneously hypertensive (SHROB) rat and the obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat. In SHROB rats we studied the ability of RB394 to prevent metabolic syndrome phenotypes, while in ZSF1 obese diabetic rats we compared RB394 with the ACE inhibitor enalapril in the treatment of type 2 diabetes and associated comorbid conditions. RB394 (10 mg/kg daily) and enalapril (10 mg/kg daily) were administered orally for 8 weeks.<br />Results: RB394 blunted the development of hypertension, insulin resistance, hyperlipidaemia and kidney injury in SHROB rats and reduced fasting blood glucose and HbA <subscript>1c</subscript> , improved glucose tolerance, reduced blood pressure and improved lipid profiles in obese ZSF1 rats. A reduction in liver fibrosis and hepatosteatosis was evident in RB394-treated obese ZSF1 rats. Unlike RB394, enalapril did not demonstrate any positive effects in relation to diabetes, hyperlipidaemia or liver dysfunction in obese ZSF1 rats. RB394 ameliorated diabetic nephropathy by reducing renal interstitial fibrosis and renal tubular and glomerular injury in obese diabetic ZSF1 rats. Intriguingly, enalapril demonstrated a weaker action against diabetic nephropathy in obese ZSF1 rats.<br />Conclusions/interpretation: These findings demonstrate that a novel sHE inhibitor/PPAR-γ agonist molecule targets multiple risk factors of the metabolic syndrome and is a glucose-lowering agent with a strong ability to treat diabetic complications.
- Subjects :
- Animals
Diabetes Mellitus, Experimental complications
Diabetic Nephropathies physiopathology
Disease Models, Animal
Enalapril pharmacology
Fatty Liver drug therapy
Fatty Liver pathology
Glucose Tolerance Test
Hypertension drug therapy
Insulin Resistance
Kidney Glomerulus pathology
Liver Cirrhosis pathology
Male
Metabolic Syndrome drug therapy
Mice
Mice, Inbred C57BL
Obesity physiopathology
Rats
Rats, Zucker
Diabetes Mellitus, Experimental drug therapy
Diabetes Mellitus, Type 2 drug therapy
Enzyme Inhibitors pharmacology
Epoxide Hydrolases antagonists & inhibitors
PPAR gamma agonists
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0428
- Volume :
- 61
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Diabetologia
- Publication Type :
- Academic Journal
- Accession number :
- 30032428
- Full Text :
- https://doi.org/10.1007/s00125-018-4685-0