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Abstract
This review will provide insight on the current understanding of the regulation of
insulin signaling in both physiological and pathological conditions through modulations
that occur with regards to the functions of the insulin receptor substrate 1 (IRS1).
While the phosphorylation of IRS1 on tyrosine residue is required for insulin-stimulated
responses, the phosphorylation of IRS1 on serine residues has a dual role, either
to enhance or to terminate the insulin effects. The activation of PKB in response
to insulin propagates insulin signaling and promotes the phosphorylation of IRS1 on
serine residue in turn generating a positive-feedback loop for insulin action. Insulin
also activates several kinases and these kinases act to induce the phosphorylation
of IRS1 on specific sites and inhibit its functions. This is part of the negative-feedback
control mechanism induced by insulin that leads to termination of its action. Agents
such as free fatty acids, cytokines, angiotensin II, endothelin-1, amino acids, cellular
stress and hyperinsulinemia, which induce insulin resistance, lead to both activation
of several serine/threonine kinases and phosphorylation of IRS1. These agents negatively
regulate the IRS1 functions by phosphorylation but also via others molecular mechanisms
(SOCS expression, IRS degradation, O-linked glycosylation) as summarized in this review.
Understanding how these agents inhibit IRS1 functions as well as identification of
kinases involved in these inhibitory effects may provide novel targets for development
of strategies to prevent insulin resistance.