Hispidulin: A potential antihyperglycemic and anti-oxidant agent-mechanistic insights into its modulatory effects on PI۳K, AKT, mTOR, IRS۱, GSK-۳β, and GLUT-۴ pathways through in vitro and in vivo studies

Objective(s): Hispidulin, a naturally occurring flavonoid with neuroprotective and anticancer properties, has shown therapeutic potential for the treatment of metabolic disorders, including diabetes mellitus. This study was designed to explore the anti-diabetic efficacy of hispidulin by examining its role in regulating glycemic markers, insulin responsiveness, oxidative stress, and the inflammatory response, and by evaluating transcriptional profiling of pivotal genes involved in the PI۳K/AKT signaling cascade.Materials and Methods: Experimental induction of type ۲ diabetes was achieved using a high-fat diet regimen, followed by intraperitoneal administration of nicotinamide ۱۱۰ mg/kg and streptozotocin ۵۵ mg/kg. Following diabetes induction, rats were treated with hispidulin (۱۰–۲۰ mg/kg orally/day). Over ۲۸ days, various parameters were assessed, including Fasting blood glucose, serum glucose, serum insulin, HOMA-IR, HOMA-β, QUICKI, CISI, oxidative stress markers (TAC, TOS, TBRAS, SOD, CAT, NO), and inflammatory cytokines (IL-۶, TNF-α, CRP, NFkB). Gene expression levels of PI۳K, AKT, mTOR, IRS-۱, GSK-۳β, and GLUT-۴ were determined via qRT-PCR.Results: Hispidulin treatment significantly (P<۰.۰۰۱) enhanced glycemic regulation and insulin sensitivity, as reflected by decreased fasting blood glucose levels and improved insulin indices. It favorably modulated oxidative stress markers and reduced the pro-inflammatory cytokines. Gene expression analysis indicated up-regulation of PI۳K, AKT, mTOR, IRS-۱, and GLUT-۴, with down-regulation of GSK-۳β, suggesting up-regulation of the PI۳K/AKT signaling cascade.Conclusion: Hispidulin exhibits potent antidiabetic properties by improving insulin sensitivity, reducing oxidative stress and inflammation, and modulating key genes in the PI۳K/AKT pathway. These findings suggest hispidulin as a therapeutic agent for managing type ۲ diabetes mellitus.

کلیدواژه ها:

Anti-oxidant activity ، Glucose transporter (GLUT) ، Hypoglycaemic effect ، Nicotinamide ، Streptozotocin