INS and Hyperglycemia: These findings suggest that in the PP zone, where Irs1 is less abundantly expressed, lack of Irs2 causes the impaired insulin signalling and increased gluconeogenesis, resulting in hyperglycaemia; in contrast, in the PV zone, where Irs1 is abundantly expressed, lack of Irs2 fails to affect insulin signalling, resulting in the maintenance of lipid synthesis, and storage and development of steatosis (Figs 1d–f and 2a,b,e,f).