It is well known that Irs2 expression is suppressed by insulin signaling itself at the transcriptional level through the insulin response element via inactivated FoxO or activated SREBP proteins [159,160,161,162,163], suggesting that hyperinsulinemia, which is common in obesity, metabolic syndrome, T2DM, and NAFLD, could cause hepatic insulin resistance by downregulation of Irs2. This evidence concerns the gene IRS2 and metabolic dysfunction-associated steatotic liver disease.