FIGURE 4 Insulin signaling and insulin resistance. Insulin signaling involves binding of insulin to its receptor followed by a cascade of intracellular events, depicted as activation pathways. Negative modulation of insulin action can be mediated via various pathways leading to insulin resistance: Various inhibitory triggers influence their respective signal modulators (partly via transcription factors), which lead via deactivating pathways (tyrosine phosphatases, serine kinases, lipid phosphatases, and degradation pathways) to inhibitory actions on insulin signaling (activation pathways). Adiponectin has an ameliorating function on glucose metabolism apart from insulin signaling.
downstream of the IRS proteins (for example, PKB/akt). Recent research indicates that several of these mechanisms underlie "insulin resistance."
The positive effects on downstream responses exerted by tyrosine phosphorylation of the receptor and the IRS proteins are opposed by dephosphorylation of these tyrosine side-chains by cellular protein-tyrosine phosphatases (PTPs) and by protein phosphorylation on serine and threonine residues (which often occur together) (15). PTP1B is a widely expressed PTP, which has been shown to play an important role in the negative regulation of insulin signaling (16).
Serine/threonine phosphorylation of IRS-1 reduces its ability to act as a substrate for the tyrosine kinase activity of the insulin receptor and inhibits its coupling to its major downstream effector systems. Multiple IRS serine kinases have been identified, including various mitogen-activated protein kinases (MAPK/ERK), c-Jun NH3-terminal kinase (JNK), atypical protein kinase C, phosphatidylinositol 3'-kinase, among others (14). Signal down-regulation can also occur via internalization and loss of the insulin receptor from the cell surface and degradation of IRS proteins (17). Members of the "suppressor of cytokine signaling" (SOCS) family of proteins participate in IRS protein degradation through a ubiquitin proteosomal pathway (18).
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