Hispidulin: A potential antihyperglycemic and anti-oxidant agent-mechanistic insights into its modulatory effects on PI3K, AKT, mTOR, IRS1, GSK-3β, and GLUT-4 pathways through in vitro and in vivo studies

Articles in Press

Document Type : Original Article

Authors

1 Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, 38000, Pakistan

2 Department of Pharmacy, Faculty of Health and Pharmaceutical Sciences, University of Agriculture Faisalabad, 38000, Pakistan

3 Department of Biochemistry, University of Agriculture Faisalabad, 38000, Pakistan

10.22038/ijbms.2025.88589.19136

Abstract

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 PI3K/AKT signaling cascade.
Materials and Methods: Experimental induction of type 2 diabetes was achieved using a high-fat diet regimen, followed by intraperitoneal administration of nicotinamide 110 mg/kg and streptozotocin 55 mg/kg. Following diabetes induction, rats were treated with hispidulin (10–20 mg/kg orally/day). Over 28 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-6, TNF-α, CRP, NFkB). Gene expression levels of PI3K, AKT, mTOR, IRS-1, GSK-3β, and GLUT-4 were determined via qRT-PCR.
Results: Hispidulin treatment significantly (P<0.001) 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 PI3K, AKT, mTOR, IRS-1, and GLUT-4, with down-regulation of GSK-3β, suggesting up-regulation of the PI3K/AKT signaling cascade.
Conclusion: Hispidulin exhibits potent antidiabetic properties by improving insulin sensitivity, reducing oxidative stress and inflammation, and modulating key genes in the PI3K/AKT pathway. These findings suggest hispidulin as a therapeutic agent for managing type 2 diabetes mellitus.

Keywords

Main Subjects

References

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Iranian Journal of Basic Medical Sciences

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Available Online from 28 December 2025

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