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

Autor: Lauren L. Kolb, René Blöcher, Markus Hartmann, Abdul H. Khan, John D. Imig, Melissa Skibba, Ewgenij Proschak
Rok vydání: 2018
Předmět:
Liver Cirrhosis
Male
0301 basic medicine
medicine.medical_specialty
Endocrinology
Diabetes and Metabolism
Kidney Glomerulus
Type 2 diabetes
030204 cardiovascular system & hematology
Article
Diabetes Mellitus
Experimental
Diabetic nephropathy
Mice
03 medical and health sciences
0302 clinical medicine
Insulin resistance
Enalapril
Diabetes mellitus
Internal medicine
Internal Medicine
medicine
Animals
Diabetic Nephropathies
Obesity
Enzyme Inhibitors
Epoxide Hydrolases
Metabolic Syndrome
Glucose tolerance test
medicine.diagnostic_test
business.industry
Glucose Tolerance Test
medicine.disease
Rats
Rats
Zucker
Fatty Liver
Mice
Inbred C57BL
PPAR gamma
Disease Models
Animal
030104 developmental biology
Endocrinology
Diabetes Mellitus
Type 2
Hypertension
ACE inhibitor
Insulin Resistance
Metabolic syndrome
business
medicine.drug
Zdroj: Diabetologia. 61:2235-2246
ISSN: 1432-0428
0012-186X
DOI: 10.1007/s00125-018-4685-0
Popis: 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. 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. RESULTS: RB394 blunted the development of hypertension, insulin resistance, hyperlipidaemia and kidney injury in SHROB rats and reduced fasting blood glucose and HbA(1c), 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. 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.
Databáze: OpenAIRE
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