Insulin vs glucagon signalling: receptors and effects
Insulin vs glucagon: two islet hormones, two receptor families, and three target tissues. Why a glucagon injection rescues hypoglycaemia through the liver, not muscle.
Contrast the receptor mechanisms and metabolic effects of insulin and glucagon in liver, muscle and adipose tissue.
The short version
- Insulin comes from beta cells and glucagon from alpha cells of the pancreatic islets; the insulin to glucagon ratio sets the metabolic direction.
- Insulin signals through a receptor tyrosine kinase, IRS, PI3K, PIP₃ and Akt; in muscle and fat, Akt sends GLUT4 vesicles to the cell surface.
- Glucagon signals through a seven-transmembrane receptor coupled to Gₛ, adenylyl cyclase, cyclic AMP and protein kinase A.
- The glucagon receptor sits mainly on the liver and is not expressed on human skeletal muscle cells, so glucagon acts on the liver.
- A glucagon injection raises blood glucose because the liver releases glucose, and it works best if the liver still has glycogen.
Insulin vs glucagon: one islet, two hormones
A man with type 1 diabetes is found sweating and confused after a missed lunch, too drowsy to swallow. Paramedics inject glucagon into his thigh and his glucose climbs. Yet glucagon does nothing inside his muscle. So how does it rescue him?
This lesson contrasts insulin vs glucagon: how each hormone signals, and what each does in liver, muscle and fat. Both come from the pancreatic islets: insulin from beta cells, glucagon from alpha cells.[1][2]
Think of them as opposites. After a carbohydrate meal, insulin rises and glucagon falls. In a fast, glucagon rises and insulin falls.[1][2]
The balance between them, the insulin to glucagon ratio, sets the metabolic direction.[2]
So the useful question for any tissue is which hormone it responds to, and through which receptor. The rest of the lesson answers that for liver, muscle and fat, starting with insulin.
Insulin signalling: receptor tyrosine kinase to Akt
Insulin binds a receptor tyrosine kinase at the cell surface. Binding switches on the kinase, which phosphorylates the receptor itself and then the insulin receptor substrates (IRS).[3][1]
The substrates recruit PI3K, which makes PIP₃, which activates Akt, the central kinase of the pathway.[3]
- Insulin binds the receptorThe receptor is a tyrosine kinase at the cell surface.
- Autophosphorylation and IRSThe kinase phosphorylates the receptor itself, then the insulin receptor substrates.
- PI3K and PIP₃The substrates recruit PI3K, which makes PIP₃.
- AktPIP₃ activates Akt, the central kinase of the pathway.
- GLUT4 in muscle and fatAkt sends vesicles carrying GLUT4 to the cell surface, and glucose enters by facilitated diffusion.
In muscle and fat, Akt sends vesicles carrying GLUT4 to the cell surface, and glucose enters by facilitated diffusion.[3][1]
What insulin does in muscle, fat and liver
- Muscle: glucose is stored as glycogen, and insulin also favours protein synthesis.[1][8][10]
- Fat: insulin stores triglyceride. When insulin is low, stored fat is broken down and fatty acids are released.[6][9]
- Liver: insulin shifts the cell from making glucose to storing it: more glycogen, less glycogen breakdown and less gluconeogenesis.[1][7]
The pattern is the same: with insulin high, fuel is stored; with insulin low, the liver releases glucose and fat releases fatty acids.[1][6]
In the liver, the result is less glucose output: insulin switches the cell from making glucose to storing it, so it lowers hepatic glucose output.[1][7]
Glucagon signalling: Gₛ, cyclic AMP and PKA
Glucagon binds a different kind of receptor, a seven-transmembrane receptor coupled to a Gₛ protein. Gₛ activates adenylyl cyclase, which makes cyclic AMP, which activates protein kinase A (PKA).[4][5]
| Insulin | Glucagon | |
|---|---|---|
| Source | Beta cells of the islets | Alpha cells of the islets |
| Receptor | Receptor tyrosine kinase | Seven-transmembrane receptor coupled to Gₛ |
| Signal | Tyrosine phosphorylation: IRS, PI3K, PIP₃, Akt | Cyclic AMP: adenylyl cyclase, PKA |
| Main targets | Muscle, fat and liver | Liver |
In short: insulin signals through tyrosine phosphorylation; glucagon signals through cyclic AMP.[3][4]
Two receptor families, two signalling styles: that is the contrast to carry into the exam. Between these two hormones, a receptor tyrosine kinase, PI3K or Akt points to insulin; Gₛ, adenylyl cyclase or cyclic AMP points to glucagon.
Why a glucagon injection works: the liver, not muscle
That answers the opening question. The glucagon receptor sits mainly on the liver, and human skeletal muscle cells do not express it.[5][4]
In the liver, protein kinase A drives glycogen breakdown and gluconeogenesis, and suppresses glycogen synthesis and glycolysis.[4][1][2]
With low insulin, glucagon also promotes ketone production.[2][4][9] Its effect on human fat is still debated, so remember the liver as its target.[5]
A day in the body: fed versus fasting
Run it as a day. After a carbohydrate meal, insulin is high and glucagon is low: muscle and fat take up glucose and the liver stores it.
Overnight it flips: the liver breaks down glycogen and makes glucose, and fat releases fatty acids.
| After a carbohydrate meal | Overnight fast | |
|---|---|---|
| Insulin and glucagon | Insulin high, glucagon low | Glucagon high, insulin low |
| Muscle and fat | Take up glucose | Fat releases fatty acids |
| Liver | Stores glucose | Breaks down glycogen and makes glucose |
Practice question
Original · USMLE styleA 27-year-old woman with type 1 diabetes mellitus is found confused and diaphoretic at home after injecting her mealtime insulin and not eating. Her fingerstick glucose concentration is 38 mg/dL. She is unable to swallow, and paramedics administer glucagon intramuscularly. Her blood glucose concentration rises over the next several minutes and her mental status improves.
Common questions
What is the difference between insulin and glucagon signalling?
Insulin binds a receptor tyrosine kinase and signals through IRS, PI3K, PIP₃ and Akt. Glucagon binds a seven-transmembrane receptor coupled to Gₛ and signals through adenylyl cyclase, cyclic AMP and protein kinase A.
Which cells make insulin and glucagon?
Insulin comes from beta cells and glucagon from alpha cells of the pancreatic islets.
Why does glucagon not act on muscle?
The glucagon receptor sits mainly on the liver, and human skeletal muscle cells do not express it, so glucagon has no direct action there.
How does insulin move glucose into muscle and fat?
Akt sends vesicles carrying GLUT4 to the cell surface, and glucose enters by facilitated diffusion.
Why does a glucagon injection raise blood glucose?
Glucagon acts on the liver, where protein kinase A drives glycogen breakdown and gluconeogenesis, so the liver releases glucose. It works best if the liver still has glycogen to release.
Transcript
Read the full narration, by chapter642 words
0:00The case: glucagon rescues him, but not through muscle
A man with type one diabetes is found sweating and confused after a missed lunch, too drowsy to swallow. Paramedics inject glucagon into his thigh, and his glucose climbs. Yet glucagon does nothing inside his muscle. So how does it rescue him? Today: contrast how insulin and glucagon signal, and what each does in liver, muscle and fat. Both hormones come from the pancreatic islets:
0:24One islet, two hormones: the insulin to glucagon ratio
insulin from beta cells, glucagon from alpha cells. Think of them as opposites. After a carbohydrate meal, insulin rises and glucagon falls. In a fast, glucagon rises and insulin falls. The balance between them, the insulin to glucagon ratio, sets the metabolic direction. Insulin first.
0:49Insulin: receptor tyrosine kinase, IRS, PI3K, PIP3, Akt
It binds a receptor tyrosine kinase at the cell surface. Binding switches on the kinase, which phosphorylates the receptor itself, and then the insulin receptor substrates. Those recruit PI3 kinase, which makes PIP3, which activates Akt, the central kinase of the pathway.
1:11GLUT4 vesicles and glucose entry in muscle and fat
In muscle and fat, Akt sends vesicles carrying GLUT4 to the cell surface, and glucose enters by facilitated diffusion. In muscle, that glucose is stored as glycogen
1:21Insulin in muscle, fat and liver
and insulin also favours protein synthesis. In fat, insulin stores triglyceride. When insulin is low, stored fat is broken down and fatty acids are released. In the liver, insulin shifts the cell from making glucose to storing it: more glycogen, less glycogen breakdown, less gluconeogenesis. Now glucagon.
1:47Glucagon: seven-transmembrane receptor, Gs, cAMP, PKA
It binds a different kind of receptor, a seven-transmembrane receptor coupled to a G s protein. G s activates adenylyl cyclase, which makes cyclic AMP, which activates protein kinase A. Insulin signals through tyrosine phosphorylation; glucagon signals through cyclic AMP. And that answers our hook.
2:10Why the injection works: the liver, not muscle
The glucagon receptor sits mainly on the liver, and human skeletal muscle cells do not express it. In the liver, protein kinase A drives glycogen breakdown and gluconeogenesis, and suppresses glycogen synthesis and glycolysis. With low insulin, glucagon also promotes ketone production. Its effect on human fat is still debated, so remember the liver as its target. That is why a glucagon injection works: the liver releases glucose, and it works best if the liver still has glycogen to release.
2:47A day in the body: fed versus fasting
Run it as a day. After a carbohydrate meal, insulin is high and glucagon is low: muscle and fat take up glucose and the liver stores it. Overnight it flips: the liver breaks down glycogen and makes glucose, and fat releases fatty acids. Your turn.
3:06Practice question
A 27-year-old woman with type one diabetes is found confused at home after taking her mealtime insulin and not eating, and her glucose is 38 milligrams per decilitre. She cannot swallow, so she is given intramuscular glucagon. Which pathway in her liver cells most directly raises glucose output? A, G s activation of adenylyl cyclase, raising cyclic AMP. B, tyrosine kinase activation of the PI three kinase and Akt pathway. C, G i inhibition of adenylyl cyclase. D, insertion of GLUT4 into the plasma membrane. E, binding of an intracellular receptor that alters gene transcription. Pause here and decide.
4:01The wrong options first, then the answer
B is out: that is the insulin pathway, which lowers liver glucose output. C is out: G i would lower cyclic AMP, and glucagon raises it. D is out: GLUT4 belongs to the insulin pathway in muscle and fat, and muscle has no glucagon receptor. E is out: that describes steroid and thyroid hormone receptors; glucagon is a peptide acting at a surface receptor. So the answer is A. Glucagon's G s coupled receptor raises cyclic AMP and protein kinase A, which drives liver glycogen breakdown and gluconeogenesis.
4:43Recap: three things to keep
Three things to keep. One: insulin uses a tyrosine kinase, PI3 kinase and Akt; muscle and fat then insert GLUT4. Two: glucagon uses G s and cyclic AMP, and acts on the liver, not muscle. Three: the insulin to glucagon ratio sets fed or fasting metabolism.
5:08Next: DKA vs HHS
Next, what happens when insulin runs short: diabetic ketoacidosis versus the hyperosmolar state.
Sources
Numbers in the text, e.g. [1], point here- OpenStax. Anatomy and Physiology 2e, 17.9 The Endocrine Pancreas. openstax.org/books/anatomy-and-physiology-2e/pages/17-9-the-endocrine-pancreas
- Repositioning Glucagon Action in the Physiology and Pharmacology of Diabetes. Diabetes 2020. europepmc.org/article/PMC/PMC7085250
- Insulin signalling and GLUT4 trafficking in insulin resistance. Biochem Soc Trans 2023. europepmc.org/article/PMC/PMC10317183
- Glucagon Receptor Signaling and Glucagon Resistance. Int J Mol Sci 2019. europepmc.org/article/PMC/PMC6651628
- Glucagon Receptor Signaling and Lipid Metabolism. Front Physiol 2019. europepmc.org/article/PMC/PMC6491692
- Partial inhibition of adipose tissue lipolysis improves glucose metabolism. PLoS Biol 2013. europepmc.org/article/PMC/PMC3576369
- Effects of insulin on the metabolic control of hepatic gluconeogenesis in vivo. Diabetes 2009. europepmc.org/article/PMC/PMC2780867
- Skeletal muscle insulin resistance in three dimensions. Cells 2026. europepmc.org/article/PMC/PMC13703090
- Ketogenesis as a metabolic checkpoint in MASLD. Metabolites 2026. europepmc.org/article/PMC/PMC13608895
- Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes. Diabetes Metab Syndr Obes 2014. europepmc.org/article/PMC/PMC3928478
- The contribution of hormone sensitive lipase to adipose tissue lipolysis and its regulation by insulin in periparturient dairy cows. Sci Rep 2018. europepmc.org/article/PMC/PMC6127149
- Glucagon, cyclic AMP, and hepatic glucose mobilization: A half-century of uncertainty. Physiol Rep 2022. europepmc.org/article/PMC/PMC9107925
The lesson teaches the standard exam pathway for glucagon, Gs, adenylyl cyclase, cAMP and PKA. Some reviews describe an additional Gq/PLC arm; it is outside this lesson.
The practice question is original and its patient is synthetic. Every fact is checked against the sources above in independent accuracy reviews. Always follow your local guidelines and your own laboratory’s ranges.
Image credits. Illustrations: Servier Medical Art (smart.servier.com), CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/), adapted (recoloured, outlined): lying man, ambulance, syringe, muscle, islet of Langerhans, cell membrane, fat tissue, liver. The receptors, cascades, vesicles, graph, see-saw, table, question card and all handwriting are drawn in code (original). No AI-generated teaching images.
Corrections. None so far. Spotted an error? Email info@medservatory.com with the lesson code MS-S1-ENDO-001.
For exam study only, not medical advice. Read the medical disclaimer.
In this series
Playlist on YouTube- EP 01Hypothalamic-pituitary axes and feedback: primary, secondary, tertiary5:05
- EP 02Primary vs secondary endocrine disorders: paired hormone levels5:13
- EP 03Insulin secretion in the beta cell: from glucose to granule5:06
- EP 04Insulin vs glucagon signalling: receptors and effects5:19
- EP 05DKA vs HHS pathophysiology: why only one makes acid5:58
- EP 06Diabetes drugs by mechanism: where each class acts5:58
- EP 07Thyroid hormone synthesis, step by step5:14
- EP 08Calcium homeostasis: PTH, vitamin D and calcitonin5:28
- EP 09Adrenal steroidogenesis: zones, enzymes and the 17α-hydroxylase fork5:29
- EP 10Congenital adrenal hyperplasia: three enzymes, three patterns5:44
- EP 11Cushing syndrome: the dexamethasone suppression test and ACTH5:29
- EP 12Primary hyperaldosteronism: high aldosterone, low renin5:27
- EP 13SIADH vs diabetes insipidus: central vs nephrogenic DI5:44
- EP 14MEN1, MEN2A and MEN2B: match the gene to its tumours5:13