Co-administration of metformin and gallic acid modulates JAK/STAT signaling pathway and glutathione metabolism in fructose-fed streptozotocin diabetic Rats

Abstract

BackgroundIncidence of diabetes Mellitus (DM) is on the rise with each passing year in spite of available therapies in the management of DM. Metformin, a standard antidiabetic drug, and gallic acid (GA) are some of the compounds with established antidiabetic properties. However, there is dearth of information on their combination on JAK/STAT signaling pathway and glutathione metabolism in diabetic model. This study investigated the combined effect of metformin and GA on diabetic rats. MethodsForty male wistar rats were divided into 5 groups viz: diabetic control, normal control, Metformin (100 mg/kg), GA (100 mg/kg) and GA (100 mg/kg) + Metformin (100 mg/kg). Diabetes was induced by administration of 10% fructose for 14 days followed by injection of streptozotocin (40 mg/kg). The therapy was administered for a total of 21 days. The pancreatic mRNA expression of antioxidant genes (glutamate cysteine ligase catalytic subunits (GCLC), glutamate cysteine ligase modifier subunits (GCLM) and Glutathione Synthetase (GSS), inflammatory genes (tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6) and proteins of the Janus Kinase/ Signal Transducer and Activator of Transcription pathway (Janus Kinase (JAK), Signal Transducer and Activator of Transcription (STAT), were quantified using reverse-transcriptase polymerase chain reaction (RT-PCR). Metformin and GA were also docked with Insulin, GSS, and Janus Kinase 2 (JAK2) to determine their binding affinity. ResultsRats treated with co-administration of GA and metformin significantly (p < 0.05) decreased fasting blood glucose level in comparison with groups treated with gallic acid only and metformin only. The gene expression analysis shows that co-administering metformin and gallic acid protects the pancreas of STZ-induced rats by increasing glutathione production, alleviating inflammation (IL-1, IL-6, IFN-), and modulating the JAK/STAT signaling pathway though upregulation of GCLC, GCLM, GSS mRNA expression and IL-1, IL-6, TNF-α, JAK2, STAT3 and STA5 mRNA expression. ConclusionThis study showed that the combination therapy of metformin and GA modulated JAK/STAT pathway mediated by the cytokines, and replenished glutathione in the pancreas of diabetic rats.