The selective control of glycolysis, gluconeogenesis and glycogenesis by temporal insulin patterns

Insulin governs systemic glucose metabolism, including glycolysis, gluconeogenesis and glycogenesis, through temporal change and absolute concentration. However, how insulin‐signalling pathway selectively regulates glycolysis, gluconeogenesis and glycogenesis remains to be elucidated. To address this issue, we experimentally measured metabolites in glucose metabolism in response to insulin. Step stimulation of insulin induced transient response of glycolysis and glycogenesis, and sustained response of gluconeogenesis and extracellular glucose concentration (GLC ex ). Based on the experimental results, we constructed a simple computational model that characterises response of insulin‐signalling‐dependent glucose metabolism. The model revealed that the network motifs of glycolysis and glycogenesis pathways constitute a feedforward (FF) with substrate depletion and incoherent feedforward loop (iFFL), respectively, enabling glycolysis and glycogenesis responsive to temporal changes of insulin rather than its absolute concentration. In contrast, the network motifs of gluconeogenesis pathway constituted a FF inhibition, enabling gluconeogenesis responsive to absolute concentration of insulin regardless of its temporal patterns. GLC ex was regulated by gluconeogenesis and glycolysis. These results demonstrate the selective control mechanism of glucose metabolism by temporal patterns of insulin. The regulation of glucose metabolism by pulse stimulations of insulin is compared with the effect of ramp stimulations. Specific network motifs mediate the differential response to these temporal patterns of stimulations that mimic in vivo patterns of insulin secretion. Synopsis The regulation of glucose metabolism by pulse stimulations of insulin is compared with the effect of ramp stimulations. Specific network motifs mediate the differential response to these temporal patterns of stimulations that mimic in vivo patterns of insulin secretion. Temporal patterns and absolute concentration of insulin selectively control glycolysis, gluconeogenesis and glycogenesis through the different network motif in FAO hepatoma cells. Step stimulation of insulin induces the transient responses and adaptations of glycolysis (via F16P) and glycogenesis through a feedforward with substrate depletion and though an incoherent feedforward loop, respectively, and induces the sustained response of gluconeogenesis (via PEPCK) through a feedforward inhibition. Pulse stimulation of insulin, like a