Indeed, if the pro-steatosis, pro-inflammatory and profibrogenic role of HIF2α in the liver has been unequivocally shown, it should be noted that HIF-2α activation can also significantly ameliorate hyperglycemia, either through the insulin-dependent pathway, with increased insulin receptor substrate-2 (IRS2), or the insulin-independent pathway, with the repression of glucagon action [134,135,136]. The gene discussed is IRS2; the disease is Hyperglycemia.