Hybrid drug combination: Anti-diabetic treatment of type 2 diabetic Wistar rats with combination of ellagic acid and pioglitazone

Background: Pioglitazone is an effective drug for the treatment of type 2 diabetes. The drug was suspended from Indian market in June 2013 due to the risk of bladder cancer but was reintroduced in July 2013 because its benefits outweighed the risks. The risks associated with pioglitazone can be minimized if its dose is reduced. Hypothesis: Ellagic acid, a polyphenolic antioxidant, is reported to reduce blood sugar in diabetic rats. The mechanism of anti-diabetic action of ellagic acid is not known. Drugs with same pharmacological action but different mechanism may act in synergistic way when combined together. The combination of ellagic acid with pioglitazone could enhance its activity and hence reduce its dose. Study design and methods: Diabetes was induced in Wistar rats by intraperitoneal administration of 175 mg of nicotinamide/kg body weight in combination with 65 mg of streptozotocin/kg body weight and then fed with high fat diet for 4 weeks (Group II-VII). Non-diabetic rats were fed with normal chow diet (Group I). Group I and II received vehicle only whereas group III to VII received ellagic acid, pioglitazone or their combination. The treatment was given orally once a day for 21 days. Results: The induction of type 2 diabetes in rats caused increase in blood glucose, LDL, triglyceride, and cholesterol and decrease in HDL. The diabetic rats showed improvement in hyperglycemia, dyslipidemia, liver and kidney function markers after treatment with ellagic acid, pioglitazone or their combinations. A combination of 10 mg of ellagic acid/kg BW with 10 mg of pioglitazone/kg BW resulted in significant improvement in all the biochemical parameters when compared to any of the individual treatment. The treatment of diabetic rats with the same combination significantly increased the expression levels of GLUT4, PPAR-gamma and adiponectin in skeletal muscle. Conclusion: The present study indicates that the dose of pioglitazone, required to achieve normoglycemia in diabetic rats, can be reduced by two folds by combining it with ellagic acid. The combinations reported here can be superior, since dose associated side effects and toxicity of the pioglitazone can be reduced.