These data suggest that the lack of both Irs1 and Irs2 in the liver significantly interrupts insulin signalling in the PP and PV zones, resulting in ‘total insulin resistance', which results in accelerated gluconeogenesis in the PP zone associated with marked hyperglycaemia, and reduced lipid synthesis and storage in the PV zone associated with prevention of steatosis. Here, INS is linked to Hyperglycemia.