A novel dual PPAR-γ agonist/sEH inhibitor treats diabetic complications in a rat model of type 2 diabetes.

Abstract

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. 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 (10mg/kg daily) and enalapril (10mg/kg daily) were administered orally for 8weeks. RB394 blunted the development of hypertension, insulin resistance, hyperlipidaemia and kidney injury in SHROB rats and reduced fasting blood glucose and HbA1c, 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. 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.