Insulin constitutes a principal evolutionarily conserved hormonal axis for maintaining glucose homeostasis(1-3); dysregulation of this axis causes diabetes(2,4). PGC-1 alpha(peroxisome-proliferator-activated receptor-gamma coactivator-1 alpha) links insulin signalling to the expression of glucose and lipid metabolic genes(5-7). The histone acetyltransferase GCN5 (general control non-repressed protein 5) acetylates PGC-1 alpha and suppresses its transcriptional activity, whereas sirtuin 1 deacetylates and activates PGC-1 alpha(8,9). Although insulin is a mitogenic signal in proliferative cells(10,11), whether components of the cell cycle machinery contribute to its metabolic action is poorly understood. Here we report that in mice insulin activates cyclin D1-cyclin-dependent kinase 4 (Cdk4), which, in turn, increases GCN5 acetyltransferase activity and suppresses hepatic glucose production independently of cell cycle progression. Through a cell-based high-throughput chemical screen, we identify a Cdk4 inhibitor that potently decreases PGC-1 alpha acetylation. Insulin/GSK-3 beta (glycogen synthase kinase 3-beta) signalling induces cyclin D1 protein stability by sequestering cyclin D1 in the nucleus. In parallel, dietary amino acids increase hepatic cyclin D1 messenger RNA transcripts. Activated cyclin D1-Cdk4 kinase phosphorylates and activates GCN5, which then acetylates and inhibits PGC-1 alpha activity on gluconeogenic genes. Loss of hepatic cyclin D1 results in increased gluconeogenesis and hyperglycaemia. In diabetic models, cyclin D1-Cdk4 is chronically elevated and refractory to fasting/feeding transitions; nevertheless further activation of this kinase normalizes glycaemia. Our findings show that insulin uses components of the cell cycle machinery in post-mitotic cells to control glucose homeostasis independently of cell division.