title: The selective control of glycolysis, gluconeogenesis and glycogenesis by temporal insulin patterns.
abstract: 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.
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Noguchi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kubota
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Yugi
authors.forename: Yu
authors.initials: Y
authors.lastname: Toyoshima
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Komori
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.forename: Shinya
authors.initials: S
authors.lastname: Kuroda
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003198:Computer Simulation; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis / Q000187:drug effects*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D008112:Liver Glycogen / Q000096:biosynthesis*; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D008954:Models, Biological; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D007328:Insulin; D008112:Liver Glycogen; D005947:Glucose