In Vivo Decoding Mechanisms of the Temporal Patterns of Blood Insulin by the Insulin-AKT Pathway in the Liver

Cell Syst. 2018 Jul 25;7(1):118-128.e3. doi: 10.1016/j.cels.2018.05.013. Epub 2018 Jun 27.


Cells respond to various extracellular stimuli through a limited number of signaling pathways. One strategy to process such stimuli is to code the information into the temporal patterns of molecules. Although we showed that insulin selectively regulated molecules depending on its temporal patterns using Fao cells, the in vivo mechanism remains unknown. Here, we show how the insulin-AKT pathway processes the information encoded into the temporal patterns of blood insulin. We performed hyperinsulinemic-euglycemic clamp experiments and found that, in the liver, all temporal patterns of insulin are encoded into the insulin receptor, and downstream molecules selectively decode them through AKT. S6K selectively decodes the additional secretion information. G6Pase interprets the basal secretion information through FoxO1, while GSK3β decodes all secretion pattern information. Mathematical modeling revealed the mechanism via differences in network structures and from sensitivity and time constants. Given that almost all hormones exhibit distinct temporal patterns, temporal coding may be a general principle of system homeostasis by hormones.

Keywords: hyperinsulinemic-euglycemic clamp; information processing; insulin; insulin-AKT pathway; mathematical modeling; temporal coding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glucose / metabolism*
  • Glucose Clamp Technique / methods
  • Glucose-6-Phosphatase / metabolism
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Homeostasis / physiology
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Resistance / physiology
  • Liver / metabolism
  • Male
  • Models, Theoretical
  • Nerve Tissue Proteins / metabolism
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Insulin / metabolism
  • Signal Transduction / physiology
  • Spatio-Temporal Analysis


  • Insulin
  • Nerve Tissue Proteins
  • Foxo1 protein, rat
  • Receptor, Insulin
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Glucose-6-Phosphatase
  • Glucose