Importantly, while young p110αD933A/WT mice and WT littermates express similar levels of IRS-1 and -2 (Foukas et al, 2006), white adipose tissue and skeletal muscle of aged (80 week) p110αD933A/WT male mice tended to contain higher levels of both IRS isoforms than WT littermates (Fig 3C and Supporting Information Fig S6), consistent with a protective effect of p110α inactivation on IRS downregulation induced by age-related hyperinsulinemia. Here, IRS1 is linked to hyperinsulinism.