Inhibition of the FOXO1 transcription factor has beneficial effects on diabetic hyperglycaemia through the suppression of glucose-6-phosphatase (G6PC) activation, but it also suppresses glucokinase (GCK) inhibition, which promotes lipogenesis. Here, Langlet et al. identify SIN3A as the corepressor required for FOXO1-mediated inhibition of GCK. SIN3A ablation in mice impaired nutrient regulation of GCK without affecting other FOXO1 target genes. In primary hepatocytes from these mice, insulin-mediated FOXO1 inhibition lowered glucose production but did not induce lipogenesis. A FOXO1 inhibitor was identified which did not clear SIN3A from the GCK promoter, inhibiting glucose production without activating lipogenesis.