The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid [FFA]), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2–F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. Here, IRS2 is linked to type 2 diabetes mellitus.