FOXO1 inhibition synergizes with FGF21 to normalize glucose control in diabetic mice

•Compound 10 is a highly-selective FOXO1 inhibitor and reduces hepatic glucose production in mice.•AS1842856 has substantial off-target, FOXO1-independent activities both in vitro and in vivo.•Selective pharmacological FOXO1 inhibition improves insulin sensitivity and normalized blood glucose in db/db mice.•FOXO1 inhibition in combination with FGF21 leads to synergistic glucose lowering in β-cell-ablated diabetic mice.