Infliximab ameliorates tumor necrosis factor‐alpha‐induced insulin resistance by attenuating PTP1B activation in 3T3L1 adipocytes in vitro

Abstract

Insulin resistance is the inability to respond to insulin and is considered a key pathophysiological factor in the development of type 2 diabetes. Tumor necrosis factor-alpha (TNF-alpha) can directly contribute to insulin resistance by disrupting the insulin signalling pathway via protein-tyrosine phosphatase 1B (PTP1B) activation, especially in adipocytes. Infliximab (Remicade ) is a TNF-alpha-neutralizing antibody that has not been fully studied in insulin resistance. We investigated the effect of infliximab on TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro, and examined the possible molecular mechanisms involved. Once differentiated, adipocytes were cultured with 5 mmol L 2-deoxy-D-glucose- H and stimulated twice with 2 μmol L insulin, in the presence or absence of 5 ng/mL TNF-alpha and/or 10 ng/mL infliximab. Glucose uptake was measured every 20 minutes for 2 hour, and phosphorylated forms of insulin receptor (IR), insulin receptor substrate-2 (IRS-2), protein kinase B (AKT) and PTP1B were determined by Western blotting. TNF-alpha-treated adipocytes showed a significant 64% decrease in insulin-stimulated glucose uptake as compared with control cells, whereas infliximab reversed TNF-alpha actions by significantly improving glucose incorporation. Although IR phosphorylation remained unaltered, TNF-alpha was able to increase PTP1B activation and decrease phosphorylation of IRS-2 and AKT. Notably, infliximab restored phosphorylation of IRS-2 and AKT by attenuating PTP1B activation. This work demonstrates for the first time that infliximab ameliorates TNF-alpha-induced insulin resistance in 3T3L1 adipocytes in vitro by restoring the insulin signalling pathway via PTP1B inhibition. Further clinical research is needed to determine the potential benefit of using infliximab for treating insulin resistance in patients.

Inhibition of tumor necrosis factor-α enhanced the antifibrotic effect of empagliflozin in an animal model with renal insulin resistance

“…It also induces the lysis of activated immune cells and apoptosis in activated macrophages and T cells [71,72]. IFX has been used to treat several autoimmune and chronic inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and ulcerative colitis [73].…”

Insulin negatively regulates dedifferentiation of mouse adipocytes in vitro

“…It is known that adipose tissue in obesity secretes a high level of pro-inflammatory adipokines, such as leptin, TNFα and ILs, but few anti-inflammatory cytokines such as adipoQ. This results in metabolic disorder and chronic inflammation [23,[32][33][34]. TNFα suppresses the expression of genes that are involved in lipid and glucose metabolism such as GLUT4, hormone-sensitive lipase, adipocyte complement-related protein and those encoding transcription factors such as C/EBPα and PPARγ2 [17,35,36].…”

“…TNFα suppresses the expression of genes that are involved in lipid and glucose metabolism such as GLUT4, hormone-sensitive lipase, adipocyte complement-related protein and those encoding transcription factors such as C/EBPα and PPARγ2 [17,35,36]. TNFαtreated adipocytes stimulate lipolysis and the loss of intracellular TG [29,32]. To verify whether mutation of the TNFα gene and leptin receptor (db) gene can influence adipocyte dedifferentiation, in vitro adipogenic differentiated cells of db/db, TNFα-/-and DT mice were induced for dedifferentiation in this study.…”

Immunometabolic bases of type 2 diabetes in the severity of COVID-19

“…Obese subjects show a constant systemic proinflammatory state characterized by abnormally high circulating levels of TNF-α, IL-1β, IL-6, IL-12, and MCP-1[ 76 , 77 ]. In adipose tissue, TNF-α induces insulin resistance by activating protein-tyrosine phosphatase 1B that in turn can dephosphorylate the insulin receptor substrate-2 (IRS-2) resulting in glucose transport arrest and hyperglycemia[ 78 , 79 ]. IL-6 and the NF-κB pathway are also involved in insulin resistance and progressive loss of normal glucose tolerance[ 80 , 81 ].…”