TiO₂nanoparticles induce insulin resistance in liver-derived cells both directly and via macrophage activation

Abstract

Upon exposure, TiO(2) nanoparticles (NPs) have been recovered in internal organs such as the liver, and are proposed to cause cellular/organ dysfunction, particularly in the liver and lungs. We hypothesized that despite being considered "inert" as bulk material, TiO(2) NPs may impair insulin responses in liver-derived cells, either indirectly by inflammatory activation of macrophages, and/or by directly interfering with insulin signaling. Using qRT-PCR and conditioned medium (CM) approaches, we show that exposure to TiO(2) NPs activates macrophages' expression of TNF-α, IL-6, IL-8, IL-1α and IL-1β and the resulting CM induces insulin resistance in Fao cells. Furthermore, direct exposure of Fao cells to TiO(2) results in activation of the stress kinases JNK and p38MAP kinase, and in induction of insulin resistance at the signaling and metabolic levels. Collectively, our findings provide a proof-of-concept for the ability of man-made NPs to induce insulin resistance in liver-derived cells, an endocrine abnormality underlying some of the most common human diseases.

The Effects of Nanomaterials as Endocrine Disruptors

“…Therefore, the adverse effects on the endocrine system, potentially caused by the release of metal ions, should be more extensively evaluated in future studies. Moreover, NPs may also act by impairing the ligand-elicited signaling cascade as demonstrated by the direct interruption of insulin signaling in liver cells due to exposure to TiO 2 -NPs [110]. In this study, NPs reduced the phosphorylation on tyrosine residues of insulin receptor substrate proteins causing a decrease in the lipid messenger phosphatidylinositol 3,4,5 triphosphate wich is needed for most metabolic effects of insulin.…”

“…[110] investigated the potential role of TiO 2 -NPs in the etiology of metabolic/endocrine disorders such as obesity and closely- related IR. In this study, the exposure of Fao rat hepatoma cells to 50 and 200 μg/mL of TiO 2 -NPs impaired insulin response and induced insulin resistance through direct interference with insulin-signalling pathways and indirect inflammatory activation of the macrophages.…”

“…In another in vitro study, an increase in cell viability, ATP/ADP ratio and secretion of insulin in response to glucose stimuli was observed in isolated pancreatic islets treated with CeO 2 -NPs at a concentration of 100 nmol/L, either alone or in combination with 30 nmol/L sodium selenite [111]. These findings could possibly be ascribed to the proinflammatory action of TiO 2 -NPs [110] and to the anti-oxidant potential of CeO 2 -NPs [111] which may exert a different effect on the insulin cascade and release, respectively.…”

Nanotoxicity: A Growing Need for Study in the Endocrine System

“…Interestingly, TiO 2 NPs might impair insulin response in Fao cells, a well‐differentiated subclone derived from the rat hepatoma cell line, by indirect inflammatory activation of macrophages and/or direct interference with insulin signaling 65. For example, conditioned medium (CM) from 100 μg/mL TiO 2 NP‐treated macrophages significantly attenuated tyrosine phosphorylation of the insulin receptor substrate proteins IRS1 and IRS2 and Ser phosphorylation of GSKβ, all critically involved in the insulin‐signaling pathway.…”

“…For example, conditioned medium (CM) from 100 μg/mL TiO 2 NP‐treated macrophages significantly attenuated tyrosine phosphorylation of the insulin receptor substrate proteins IRS1 and IRS2 and Ser phosphorylation of GSKβ, all critically involved in the insulin‐signaling pathway. It is suggested that TiO 2 NP exposure impaired the cellular response to insulin stimulation in Fao cells, producing so‐called insulin resistance 65. Furthermore, direct exposure to TiO 2 NPs (50 or 200 μg/mL) affected insulin responses in liver‐derived cells and activated the stress kinases JNK and p38MAP kinase, which interfere with insulin signaling.…”