Introduction & Objective: Increasing the mass of pancreatic beta cells through neogenesis and proliferation while protecting islets from oxidative stress and inflammation is a possible therapeutic strategy for treating all types of diabetes. We examined the effect of the natural phytocompound Gymnemic Acid I (GA) on human pancreatic islets to reduce oxidative stress and inflammation.
Methods: Human pancreatic islets were exposed to various stress-induced, well-established models like hypoxia and cytokine cocktails (CC) with or without GA. Flow cytometry, Luminex assay, and RT-qPCR techniques were used to assess the oxidative stress and inflammatory markers. All the results were statistically compared with appropriate experimental controls.
Results: Treatment with GA maintained islet viability for >24 h and significantly increased (P<0.024) insulin secretion assessed by GSIS and substantially (P<0.05) upregulated beta-cell functional genes (PCSK1, SLC2A, GCK). Reactive oxygen species (ROS), hypoxia, and CC-induced cell death were all substantially reduced by GA treatment. Additionally, inflammatory, pro-apoptotic genes (HIF1A, CCL5, IL-6, INFb1, IP10, CASP3) and secretory cytokine production were considerably (P<0.05) downregulated. It protected the islets by making it easier for the transcription factor NFE2L2 to bind ARE which in turn led to a significant (P<0.05) upregulation of promotor regions encoding cytoprotective and antioxidant genes (HOMOX1, SOD1, CAT, NQO1, BCL2).
Conclusion: GA functions as an NFE2L2 activator or stabilizer, protecting and extending the viability of islets. It has improved islet function by boosting endogenous antioxidant defense enzymes, preventing oxidative damage and apoptosis in response to cellular stress driven by inflammation, hypoxia, or both. GA can serve as a treatment for improving human islet survival and function.
J. Kuncha: None. C. Darden: None. J. Kirkland: None. J.D. Mattke: None. M.C. Lawrence: None. B. Naziruddin: None.
