Figure 5.

Schematic overview of the beneficial impact of chronic p110α inactivation on age-related deterioration of insulin sensitivity. The levels of IRS are key to insulin signalling. Chronic stimulation with insulin, as occurs in hyperinsulinemia, downregulates IRS via a negative feedback loop that involves IRS phosphorylation by S6K, exacerbating age-related insulin resistance. Reduced p110α activity as a consequence of loss-of-function mutation (D933A) or pharmacologic inhibition (e.g. A66) attenuates S6K activity, protecting against chronic insulin-induced IRS depletion, thus promoting insulin sensitivity.