Storing Glucose and Switching Off the Liver's Output

Getting glucose into the cell is only half the job. Once glucose is inside, insulin decides what happens to it. In liver and muscle it activates glycogen synthase, the enzyme that links glucose units into glycogen. The route runs through Akt again: Akt inhibits GSK3, the kinase that keeps glycogen synthase switched off, so a phosphatase can turn it on. At the same time, insulin tells the liver to stop releasing glucose. It reduces production of the gluconeogenic enzymes PEPCK and G6Pase and cuts the supply of substrates like lactate and amino acids. So the fall in blood glucose comes from three sources at once: more uptake, more storage, and less release. Notice the timing: transport and enzyme changes happen in minutes, while the shutdown of gluconeogenic genes takes hours.

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How insulin switches on glycogen synthase

Glycogen synthase is kept inactive by phosphorylation. The kinase GSK3 is one of the enzymes that phosphorylates it. Insulin signaling through Akt inhibits GSK3, which allows protein phosphatase 1 to remove the inhibitory phosphates from glycogen synthase. The enzyme becomes active and adds glucose units to glycogen chains. The same logic applies in liver and in muscle, though the liver uses glycogen to buffer blood glucose for the whole body while muscle keeps it for its own contraction.

How insulin reduces hepatic glucose output

The liver releases glucose by breaking down glycogen and by making new glucose through gluconeogenesis. Insulin acts on both routes. It reduces transcription of the gluconeogenic enzymes PEPCK and G6Pase, so the liver builds less glucose from lactate, glycerol, and amino acids. It also lowers the flow of those substrates to the liver and favors storing them as glycogen or fat. Because the liver is the main source of blood glucose during fasting, this suppression is a major part of how insulin lowers blood glucose.

Two time scales of insulin action

Minutes

GLUT4 vesicle translocation and increased glucose uptake
Dephosphorylation and activation of glycogen synthase
Inhibition of GSK3 through Akt

Hours

Reduced transcription of PEPCK and G6Pase
Lower gluconeogenic substrate supply
Shift of glucose into glycogen and fat stores

Insulin lowers blood glucose through three coordinated outputs: more glucose enters muscle and adipose tissue through GLUT4, more of it is stored as glycogen, and less of it is released by the liver. The first two act within minutes; the suppression of hepatic glucose production develops over hours.