Metformin disrupts insulin secretion, causes proapoptotic and oxidative effects in rat pancreatic beta‐cells in vitro

• Published in: Journal of biochemical and molecular toxicology 2022-05, Vol.36 (5), p.e23007-n/a
• Main Authors: Valle, Maíra M.R., Vilas‐Boas, Eloisa Aparecida, Lucena, Camila F., Teixeira, Simone A., Muscara, Marcelo N., Carpinelli, Angelo R.
• Format: Article
• Language: English
• Subjects: Antidiabetics; Antioxidants; Apoptosis; beta‐cells; Biomarkers; Carbonyls; Cell cycle; Cell death; Cell survival; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Enzymes; Glucose metabolism; Glutathione; Insulin; Insulin secretion; Metabolism; Metformin; Oxidative stress; Pancreas; Reactive oxygen species; ROS; Secretion
• ISSN: 1095-6670; 1099-0461
• DOI: 10.1002/jbt.23007

Metformin is the first‐line drug to treat type 2 diabetes mellitus. Its mechanism of action is still debatable, and recent studies report that metformin attenuates oxidative stress. This study evaluated the in vitro antioxidant effects of a broad range of metformin concentrations on insulin‐producing cells. The cell cycle, metabolism, glucose‐stimulated insulin secretion, and cell death were evaluated to determine the biguanide effects on beta‐cell function and survival. Antioxidant potential was based on reactive oxygen species (ROS), reduced glutathione (GSH), oxidative stress biomarker levels, and antioxidant enzyme and transcriptional factor Nrf2 activities. The results demonstrate that metformin disrupted GSIS in a concentration‐dependent manner, lowered insulin content, and attenuated beta‐cell metabolism. At high concentrations, metformin induced cell death and cell cycle arrest as well as increased ROS generation, consequently reducing GSH content. Although carbonylated protein content was elevated, indicating oxidative stress, the antioxidant enzyme and Nrf2 activities were not altered. In conclusion, our results show that metformin disrupts pancreatic beta‐cell functionality but does not exert a putative antioxidant effect. It is important to note that the drug could potentially affect beta‐cells, especially at high circulating levels. Metformin tested in vitro in higher doses (>0.5 mM) in rat pancreatic beta cells attenuates cell metabolism, resulting in a diminished response to glucose‐stimulated insulin secretion (GSIS) and indicating cellular dysfunction. The drug also caused a redox imbalance, with higher reactive oxygen species production and oxidative stress markers (protein carbonyls). The cell cycle was disrupted, and cell death was increased, both apoptosis and necrosis. It remains to be confirmed if the higher reactive oxygen species levels participate in the loss of GSIS and cell death pathways in vivo.