While hyperinsulinemia‐via negative feedback loops‐leads to a decrease in IRS2 expression in PP and PV zones and relieve the inhibition of gluconeogenesis, it fails to downregulate IRS1 expression in the PV zone, where lipogenic processes still take place.[40] Indeed, IRS2 expression is epigenetically repressed in the livers of obese humans with type 2 diabetes.[41] Selective insulin resistance is an emerging topic in metabolic syndrome. Here, IRS2 is linked to type 2 diabetes mellitus.