Concentration‐dependent metabolic effects of metformin in healthy and Fanconi anemia lymphoblast cells

Abstract

Metformin (MET) is the drug of choice for patients with type 2 diabetes and has been proposed for use in cancer therapy and for treating other metabolic diseases. More than 14,000 studies have been published addressing the cellular mechanisms affected by MET. However, several in vitro studies have used concentrations of the drug 10-100-fold higher than the plasmatic concentration measured in patients. Here, we evaluated the biochemical, metabolic, and morphologic effects of various concentrations of MET. Moreover, we tested the effect of MET on Fanconi Anemia (FA) cells, a DNA repair genetic disease with defects in energetic and glucose metabolism, as well as on human promyelocytic leukemia (HL60) cell lines. We found that the response of wild-type cells to MET is concentration dependent. Low concentrations (15 and 150 µM) increase both oxidative phosphorylation and the oxidative stress response, acting on the AMPK/Sirt1 pathway, while the high concentration (1.5 mM) inhibits the respiratory chain, alters cell morphology, becoming toxic to the cells. In FA cells, MET was unable to correct the energetic/respiratory defect and did not improve the response to oxidative stress and DNA damage. By contrast, HL60 cells appear sensitive also at 150 μM. Our findings underline the importance of the MET concentration in evaluating the effect of this drug on cell metabolism and demonstrate that data obtained from in vitro experiments, that have used high concentrations of MET, cannot be readily translated into improving our understanding of the cellular effects of metformin when used in the clinical setting.

Inhibitory Action of Antidiabetic Drugs on the Free Radical Production by the Rod Outer Segment Ectopic Aerobic Metabolism

“…As shown in Figure 2, and as reported in the literature [36], the therapeutic doses of MTF induce an increment of the oxidative metabolism and the related oxidative stress production, which can negatively affect the OS and the retina. Therefore, we asked whether the combination of the therapeutic doses of MTF with low GLB concentrations, which showed a mild inhibitory effect on energy metabolism, could reverse such increase.…”

Immune response to influenza vaccination in the elderly is altered by chronic medication use

“…It also activates IKKα/β, reduces ROS production and blunts the secretion of pro-inflammatory cytokines [29]. Metformin increases oxidative phosphorylation and fatty acid catabolism and thereby promotes memory formation of T cells instead of their differentiation into effector cells, which preferentially use glycolysis for energy and biomass production [30, 31]. B cells also switch to glycolysis upon activation and drugs that promote pathways of energy production other than glycolysis might reduce B cell proliferation [32].…”

Genetic screening of children with marrow failure. The role of primary Immunodeficiencies

“…Western blot experiments were performed according to standard procedures. 28,29 . Cells were centrifuged to remove the growth medium at 1000g for 2 min.…”