PI3K is the dominant signalling pathway recruited by IRS proteins to mediate their effects on metabolism and growth

Insulin and Igf1 have pleiotropic effects on development, growth and metabolism. The activated insulin and IGF1 receptors engage insulin receptor substrate (IRS) proteins, intracellular adaptor molecules that recruit multiple downstream signalling pathways, including PI3K and GRB2-RAS-MAPK. Global deletion of IRS1 or IRS2 in mice results in divergent effects on growth, metabolism, and ageing. However, the precise signalling pathways recruited by IRS1 or IRS2 to mediate their physiological effects in vivo have not been defined.

We generated knock-in mice in which either IRS1 or IRS2 was mutated to prevent downstream recruitment of PI3K or GRB2 and undertook phenotypic analysis of these animals.

Knock-in mice unable to recruit PI3K to IRS1 (Irs1^YnF) or to IRS2 (Irs2^YnF) had limited or no compensation in IRS2 and IRS1 signalling respectively. Irs1^YnF mice were growth restricted, with reduced adiposity and insulin resistance, but did not develop diabetes due to compensatory increase in β-cell mass. Irs2^YnF mice were obese and insulin resistant and developed diabetes due to β-cell failure. In contrast knock-in mice unable to recruit GRB2 to IRS1 (Irs1^Y891F) or to IRS2 (Irs2^Y911F) displayed normal growth and metabolism.

PI3K recruitment by either IRS1 or IRS2 is the primary signalling mediator of the effects of these adaptor molecules on growth and metabolism in mice, and suggest that the other signalling pathways recruited by IRS1 and IRS2, including GRB2, have minimal or redundant roles.