EFFECTS OF CO-ADMINISTRATION OF GALLIC ACID AND METFORMIN ON STREPTOZOTOCIN (STZ)-INDUCED DIABETIC RATS

Abstract

Diabetes and diabetic complications such as obesity, cardiovascular disease, and dysfunction of various nerves, enzymes, organs and pathways are on the increase worldwide and there is need for effective therapeutic options. This study evaluated the effect of combining gallic acid and metformin; a standard drug in the treatment of Streptozotocin (STZ)-induced type 1 diabetic rats. Male Wistar rats were induced with type 1 diabetes by a single intraperitoneal injection of 60mg/kg body weight STZ. Then the induced groups were post-treated with gallic acid 100mg/kg body weight, Metformin 100mg/kg body weight and Gallic acid + Metformin 100mg/kg body weight for 21 days. After the period of treatments, RT-PCR was used to investigate the expression of genes involved in glutathione metabolism, pro-inflammatory cytokines and JAK2 and STAT3 in the pancreas of the experimental animals. Results showed significant elevated blood glucose in the diabetic control rats (316 mg/dl ±42.9) compared with normal control rats (100.00mg/dl ±1.71) (p<0.05) and a significant reduction in fasting blood glucose level was observed in STZ + metformin (118.00 mg/dl ±7.97), STZ + gallic acid (133.00 mg/dl ±9.39) and STZ+ gallic acid + Metformin (117.00 mg/dl ±10.87) treatment groups when compared with diabetic control group. In the pancreatic tissues, the mRNA expressions of Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) proteins were up-regulated in diabetic groups when compared with the normal control groups and there was a significant downregulation in the treatment groups. The groups treated with the combination of gallic acid dose and metformin dose significantly (p< 0.05) down-regulated the mRNA expression of JAK 2, STAT 3 and STAT5 in comparison to groups treated with gallic acid and metformin alone. Also, the pancreatic mRNA expression of pro-inflammatory genes (TNF- α, IL-1β and IL-6) were significantly (p < 0.05) down-regulated in groups treated with gallic acid (GA) co-administered with metformin, STZ + Metformin, and STZ + gallic acid when compared with diabetic control group. In addition, the treatments of diabetic rats with co-administration of metformin and GA doses, STZ + metformin and STZ + gallic acid significantly (p < 0.05) up-regulated the mRNA expression of GSS, GCLC and GCLM. Comparatively, molecular docking analysis revealed that both gallic acid and metformin had favorable binding affinities and molecular interactions with JAK2, GSS, Insulin and TNF-α. This data revealed that the co-administration of gallic acid and metformin lowered fasting blood glucose level, replenished glutathione, reduced inflammation and modulate JAK/STAT pathway in the pancreas of STZ-induced diabetic rats.