Irs1−/− have mild glucose intolerance and Irs3−/− have no detectable phenotype, but Irs1−/−/Irs3−/− are hyperglycemic and display severe lipoatrophy (Terauchi et al., 2003), indicative of their interaction in developing the type 2 diabetes phenotype. Here, IRS1 is linked to type 2 diabetes mellitus.