The intersection of metformin and inflammation

Abstract

The biguanide metformin is the most commonly used antidiabetic drug. Recent studies show that metformin not only improves chronic inflammation by improving metabolic parameters but also has a direct anti-inflammatory effect. In light of these findings, it is essential to identify the inflammatory pathways targeted by metformin to develop a comprehensive understanding of the mechanisms of action of this drug. Commonly accepted mechanisms of metformin action include AMPK activation and inhibition of mTOR pathways, which are evaluated in multiple diseases. Additionally, metformin's action on mitochondrial function and cellular homeostasis processes such as autophagy is of particular interest because of the importance of these mechanisms in maintaining cellular health. Both dysregulated mitochondria and failure of the autophagy pathways, the latter of which impair clearance of dysfunctional, damaged, or excess organelles, affect cellular health drastically and can trigger the onset of metabolic and age-related diseases. Immune cells are the fundamental cell types that govern the health of an organism. Thus, dysregulation of autophagy or mitochondrial function in immune cells has a remarkable effect on susceptibility to infections, response to vaccination, tumor onset, and the development of inflammatory and autoimmune conditions. In this study, we summarize the latest research on metformin's regulation of immune cell mitochondrial function and autophagy as evidence that new clinical trials on metformin with primary outcomes related to the immune system should be considered to treat immune-mediated diseases over the near term.

Keywords: autophagy; complex 1; inflammation; metformin; mitochondria.

Figure 1.

Model: metformin’s regulation of mitochondrial respiratory complex activity and homeostatic processes such as autophagy and mitophagy prevent cellular and mitochondrial reactive oxygen species (ROS) generation and release of mitochondrial DNA, resulting in lower proinflammatory cytokine production and improved cellular health (figure created with Biorender.com). AMPK, AMP-activated protein kinase; BNIP3, BCL2/adenovirus E1B 19 kDa interacting protein 3; LAMP1, lysosomal associated membrane protein 1; LC3, light chain protein 3; mTOR, mechanistic target of rapamycin; PINK1, PTEN-induced putative kinase 1; p62, protein 62/sequestosome 1.