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[Biochemistry](https://durgical.com/en/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

- [Glycogen metabolism](https://durgical.com/en/biochemistry/pathways/glycogen-metabolism/)
- [Gluconeogenesis](https://durgical.com/en/biochemistry/pathways/gluconeogenesis/)
- [Ketogenesis (ketone body synthesis)](https://durgical.com/en/biochemistry/pathways/ketogenesis/)

## Related conditions

- [Diabetic ketoacidosis](https://durgical.com/en/conditions/diabetic-ketoacidosis/)
- [Type 1 diabetes mellitus](https://durgical.com/en/conditions/type-1-diabetes-mellitus/)

## Related

- [G protein-coupled receptors and cAMP](https://durgical.com/en/biochemistry/topics/g-protein-coupled-receptors-and-camp/)
- [Adenylyl cyclase](https://durgical.com/en/biochemistry/enzymes/adenylyl-cyclase/)
- [Protein kinase A (PKA)](https://durgical.com/en/biochemistry/enzymes/protein-kinase-a/)
- [Cyclic AMP (cAMP)](https://durgical.com/en/biochemistry/molecules/cyclic-amp/)
- [Glycogen phosphorylase](https://durgical.com/en/biochemistry/enzymes/glycogen-phosphorylase/)
- [Glycogen synthase](https://durgical.com/en/biochemistry/enzymes/glycogen-synthase/)
- [Phosphoenolpyruvate carboxykinase (PEPCK)](https://durgical.com/en/biochemistry/enzymes/phosphoenolpyruvate-carboxykinase/)
- [Acetyl-CoA carboxylase (ACC)](https://durgical.com/en/biochemistry/enzymes/acetyl-coa-carboxylase/)
- [Carnitine palmitoyltransferase I (CPT-I)](https://durgical.com/en/biochemistry/enzymes/carnitine-palmitoyltransferase-i/)
- [Insulin signalling](https://durgical.com/en/biochemistry/topics/insulin-signalling/)
- [Adrenaline](https://durgical.com/en/biochemistry/molecules/adrenaline/)
- [Fed, fasting and starvation states](https://durgical.com/en/biochemistry/topics/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.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: [GCG: Pro-glucagon (human)](https://www.uniprot.org/uniprotkb/P01275/entry) (UniProt, 2026); [GCGR: Glucagon receptor (human)](https://www.uniprot.org/uniprotkb/P47871/entry) (UniProt, 2026); [5EE7: Crystal structure of the human glucagon receptor (GCGR) in complex with the antagonist MK-0893](https://www.rcsb.org/structure/5EE7) (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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