Biochemistry · Topic
Glucagon signalling !
Glucagon is the fasting hormone: it tells the liver to release glucose and make ketone bodies.
Updated 2026-11-01
Key facts
- Pancreatic alpha cells secrete it when glucose falls or after a protein-rich meal; glucose, insulin and somatostatin hold it back.
- Its receptor (GCGR) is mainly in the liver and couples to Gs → adenylyl cyclase → cAMP → PKA.
- Skeletal muscle has no glucagon receptor: its glycogen answers only to adrenaline, Ca²⁺ and AMP.
- PKA switches on glycogen breakdown and gluconeogenesis, and switches off glycogen synthesis, liver glycolysis and lipogenesis.
In detail
- PKA phosphorylates phosphorylase kinase, which activates glycogen phosphorylase; at the same time it phosphorylates and inactivates glycogen synthase.
- PKA phosphorylates the bifunctional enzyme PFK-2/FBPase-2: fructose 2,6-bisphosphate falls, PFK-1 slows and fructose 1,6-bisphosphatase is released; flux goes to gluconeogenesis.
- Phosphorylated liver pyruvate kinase is inactive, so phosphoenolpyruvate is not lost as pyruvate.
- Through CREB, transcription of PEPCK and glucose 6-phosphatase rises (an effect over hours, boosted by cortisol).
- With acetyl-CoA carboxylase inhibited, malonyl-CoA falls, CPT1 opens and fatty acids enter the mitochondrion: beta-oxidation and ketogenesis.
- Adrenaline uses the same cAMP cascade in the liver (β2 receptors) and also acts on muscle and through α1 receptors (Ca²⁺).
Clinical notes
- Injected glucagon raises glucose in severe hypoglycaemia only if the liver has glycogen; it helps little in starvation or after heavy drinking.
- Because it raises cAMP without going through beta receptors, glucagon is used in beta-blocker poisoning.
- Glucagonoma: an alpha-cell tumour with diabetes, weight loss and necrolytic migratory erythema.
- In diabetic ketoacidosis, high glucagon with no insulin to oppose it drives glucose and ketone production.
Pathways
Related conditions
Related
- G protein-coupled receptors and cAMP
- Adenylyl cyclase
- Protein kinase A (PKA)
- Cyclic AMP (cAMP)
- Glycogen phosphorylase
- Glycogen synthase
- Phosphoenolpyruvate carboxykinase (PEPCK)
- Acetyl-CoA carboxylase (ACC)
- Carnitine palmitoyltransferase I (CPT-I)
- Insulin signalling
- Adrenaline
- Fed, fasting and starvation states
Test yourself
Think of the answer, then tap the question to see it.
Why does glucagon not mobilise muscle glycogen?
Because skeletal muscle does not express the glucagon receptor; its glycogen answers to adrenaline, Ca²⁺ and AMP.
How does glucagon speed up gluconeogenesis through fructose 2,6-bisphosphate?
PKA phosphorylates PFK-2/FBPase-2, fructose 2,6-bisphosphate falls, PFK-1 slows and fructose 1,6-bisphosphatase is released.
Which G protein and second messenger does the glucagon receptor use?
Gs, which activates adenylyl cyclase to make cAMP.
Why does glucagon favour ketogenesis?
By inhibiting acetyl-CoA carboxylase it lowers malonyl-CoA, so CPT1 lets more fatty acids into the mitochondrion.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: GCG: Pro-glucagon (human) (UniProt, 2026); GCGR: Glucagon receptor (human) (UniProt, 2026); 5EE7: Crystal structure of the human glucagon receptor (GCGR) in complex with the antagonist MK-0893 (RCSB Protein Data Bank, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.