Tumor necrosis factor-alpha, sphingomyelinase and ceramides activate tyrosine kinase, p21Ras and phosphatidylinositol 3-kinase: implications for glucose transport and insulin resistance.

Diabetes mellitus is one of the leading causes of morbidity in North America. Insulin resistance plays a key role in the pathogenesis of Type 2 diabetes1. Insulin resistance (defined as decreased ability of insulin to stimulate glucose uptake) is normally caused by a post-receptor defect in insulin signaling which leads to glucose transport into cells. The insulin signaling pathway responsible for glucose uptake involves sequential tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrate-1 and -2 (IRS-1 and IRS-2) (Figure1). IRS-1 acts as a docking site by using specific phosphorylation motifs and SH2 domains and facilitates the activation of other proteins such as phosphatidylinositol 3-kinase (PI 3-kinase)1.