Insulin stores in the fed state, glucagon mobilises in the fasted
Expansion
| Pathway | Insulin (fed) | Glucagon (fasted) |
|---|---|---|
| Glycogen synthesis | On | Off |
| Glycogenolysis | Off | On |
| Gluconeogenesis | Off | On |
| Glycolysis | On | Off |
| Lipogenesis | On | Off |
| Lipolysis | Off | On |
| Ketogenesis | Off | On |
| Protein synthesis | On | Off |
“It is the ratio that matters, not either hormone alone.”
The key regulatory molecule is fructose-2,6-bisphosphate, controlled by the bifunctional enzyme PFK-2/FBPase-2. Insulin raises it, activating glycolysis and inhibiting gluconeogenesis; glucagon lowers it by cAMP dependent phosphorylation, doing the reverse. This is how the liver avoids running both pathways at once.
Glucagon acts almost entirely on the liver; it has little effect on muscle, which lacks glucagon receptors and, lacking glucose-6-phosphatase, cannot release glucose into the blood at all. Muscle glycogen serves muscle only.
This explains ketoacidosis: insulin’s most sensitive action is suppression of lipolysis. In insulin deficiency, unrestrained lipolysis floods the liver with fatty acids and an unopposed glucagon signal directs them to ketone bodies, which is why type 1 diabetes produces ketoacidosis while type 2, with residual insulin, tends to produce the hyperosmolar state.