Insulin resistance is associated with cardiovascular disease. Impaired insulin receptor substrate (IRS)–mediated signal transduction is a major contributor to insulin resistance. Recently, IRS-1 phosphorylation at serine 307 by stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) has been highlighted as a molecular event that causes insulin resistance. We investigated IRS-1–mediat...

See online version for legend and references. systemic IR Apparently normal intrauterine growth and development, severe hyperglycemia and hyperke-tonemia, perinatal death as the result of diabetic ketoacidosis within 48–72 hours IRS-1 Retarded embryonal and postnatal growth, insulin resistance, normal fasting glycemia and normal or mild glucose intolerance, hyperinsulinemia IRS-2 Insulin resist...

Insulin rapidly stimulates tyrosine kinase activity of its receptor resulting in phosphorylation of its cytosolic substrate, insulin receptor substrate-1 (IRS-1), which in turn associates with phosphatidylinositol 3-kinase (PI 3-kinase), thus activating the enzyme. Glucocorticoid treatment is known to produce insulin resistance, but the exact molecular mechanism is unknown. In the present study...

mTOR (mammalian target of rapamycin) responds to the presence of nutrients, energy and growth factors to link cellular metabolism, growth and proliferation. The rapamycin-sensitive mTORC (mTOR complex) 1 activates the translational regulator S6K (S6 kinase), leading to increased protein synthesis in the presence of nutrients. On the other hand, the rapamycin-insensitive mTORC2 responds to the p...

Insulin Receptor Substrate-1 (IRS-1) and IRS-2 are cytoplasmic adaptor proteins that mediate the activation of signaling pathways in response to ligand stimulation of upstream cell surface receptors. Despite sharing a high level of homology and the ability to activate Phosphatidylinositol-3-Kinase (PI3K), only Irs-2 positively regulates aerobic glycolysis in mammary tumor cells. To determine th...

As a candidate gene for type 2 diabetes (T2D), insulin receptor substrate-1 (IRS‑1) gene variations were found to be associated with the risk of T2D. The aim of our study was to investigate the contribution of promoter DNA methylation of the IRS‑1 gene to the risk of T2D. Using bisulphite pyrosequencing technology, the DNA methylation levels of 3 CpG dinucleotides within the IRS‑1 gene promoter...

In addition to a role in response to insulin and insulin-like growth factors, insulin receptor substrate 1 (IRS-1) is phosphorylated in response to IL-4, the interferons (IFNs) and oncostatin M (OSM). Here mutant cell lines lacking JAK1, JAK2, or Tyk2 were used to determine the role(s) of the Janus kinase (JAK) family of protein-tyrosine kinases in IRS-1 phophorylation. 32D cells, which do not ...

Serine/threonine phosphorylation of insulin receptor substrate-1 (IRS-1) is an important negative modulator of insulin signaling. Previously, we showed that glycogen synthase kinase-3 (GSK-3) phosphorylates IRS-1 at Ser(332). However, the fact that GSK-3 requires prephosphorylation of its substrates suggested that Ser(336) on IRS-1 was the "priming" site phosphorylated by an as yet unknown prot...

A pathway sensitive to rapamycin, a selective inhibitor of mammalian target of rapamycin (mTOR), down-regulates effects of insulin such as activation of Akt (protein kinase B) via proteasomal degradation of insulin receptor substrate 1 (IRS-1). We report here that the pathway also plays an important role in insulin-induced subcellular redistribution of IRS-1 from the low-density microsomes (LDM...

The pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) includes the development of insulin resistance and, at a later stage, impairment of b-cell response. In the past few years, different elements, including the proto-oncogene, Shc, and the insulin receptor substrate (IRS) proteins, have been found to have important roles in the insulin signaling network. Whithers et al. (1) have ...