Tumor necrosis factor alpha inhibits signaling from the insulin receptor.

TLDR

Insulin resistance, linked to infections, cancer, and type 2 diabetes, is a common problem. The study investigates how TNF‑α interferes with insulin action. TNF‑α strongly inhibits insulin‑stimulated glucose uptake, reduces insulin receptor autophosphorylation and IRS‑1 phosphorylation, and impairs insulin signaling, thereby blocking insulin’s biological actions.

Abstract

Insulin resistance is a common problem associated with infections and cancer and, most importantly, is the central component of non-insulin-dependent diabetes mellitus. We have recently shown that tumor necrosis factor (TNF) alpha is a key mediator of insulin resistance in animal models of non-insulin-dependent diabetes mellitus. Here, we investigate how TNF-alpha interferes with insulin action. Chronic exposure of adipocytes to low concentrations of TNF-alpha strongly inhibits insulin-stimulated glucose uptake. Concurrently, TNF-alpha treatment causes a moderate decrease in the insulin-stimulated autophosphorylation of the insulin receptor (IR) and a dramatic decrease in the phosphorylation of IR substrate 1, the major substrate of the IR in vivo. The IR isolated from TNF-alpha-treated cells is also defective in the ability to autophosphorylate and phosphorylate IR substrate 1 in vitro. These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin.