Glucagon Physiology

 

Glucagon is the principal counter-regulatory hormone to insulin.

 

It is released during fasting and acts mainly on the liver to increase blood glucose concentration.

 

Key point: Glucagon raises blood glucose by stimulating hepatic glycogenolysis and gluconeogenesis.

 

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Source of Glucagon

 

Glucagon is a peptide hormone produced by α cells of the islets of Langerhans.

 

It is synthesised as proglucagon and then processed to active glucagon.

 

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Stimuli for Glucagon Secretion

 

Glucagon is released when blood glucose falls.

 

Major stimuli:

• Hypoglycaemia
• Amino acids, especially alanine and arginine
• Sympathetic stimulation (adrenaline)
• Exercise

 

Inhibitors:

• Hyperglycaemia
• Insulin
• Somatostatin
• Increased free fatty acids

 

Exam rule: Low glucose stimulates glucagon release.

 

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Mechanism of Action

 

Glucagon binds to G protein-coupled receptors on hepatocytes.

 

This activates adenylate cyclase and increases intracellular cyclic AMP.

 

Cyclic AMP activates protein kinase A, which phosphorylates key metabolic enzymes.

 

Key point: Glucagon acts via the cAMP second messenger system.

 

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Major Actions of Glucagon

 

Glucagon acts mainly on the liver.

 

Its overall effect is to switch the body from nutrient storage to fuel mobilisation.

 

Glucagon:

• Increases blood glucose
• Promotes ketone production
• Increases urea synthesis

 

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Glycogenolysis

 

Glycogenolysis is the breakdown of glycogen to glucose.

 

The liver stores glycogen after meals under the influence of insulin.

 

During fasting, glucagon stimulates hepatocytes to break down glycogen:

• This produces glucose-1-phosphate, which is converted to glucose-6-phosphate.
• Hepatocytes contain glucose-6-phosphatase, which converts glucose-6-phosphate to free glucose.
• This glucose is then released into the circulation.

 

Key point: Glucagon mobilises hepatic glycogen stores to provide a rapid source of glucose.

 

Exam rule: Glycogenolysis = breakdown of glycogen to glucose.

 

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Gluconeogenesis

 

Gluconeogenesis is the synthesis of new glucose from non-carbohydrate precursors.

 

It becomes increasingly important as hepatic glycogen stores are depleted.

 

Major substrates include:

• Alanine and other amino acids
• Lactate
• Glycerol

 

Glucagon stimulates the enzymes involved in this pathway.

 

The newly synthesised glucose is released into the bloodstream.

 

Key point: Gluconeogenesis generates glucose when glycogen stores are low.

 

Exam rule: Gluconeogenesis = synthesis of glucose from amino acids, lactate, and glycerol.

 

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Effects on Protein Metabolism

 

Glucagon increases hepatic uptake of amino acids.

 

These amino acids are used for gluconeogenesis.

 

Their amino groups are removed and converted to urea.

 

As a result:

• Urea production increases
• Plasma urea concentration may rise during prolonged fasting

 

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Effects on Fat Metabolism

 

Glucagon promotes fatty acid oxidation in the liver:

• This increases acetyl-CoA production.
• Excess acetyl-CoA is converted into ketone bodies.

 

This provides an alternative fuel source during fasting.

 

Key point: Glucagon promotes ketogenesis during prolonged fasting.

 

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Effects on Hepatic Metabolism

 

Substance	Effect of Glucagon
Glycogen	Increased breakdown (glycogenolysis)
Glucose	Increased hepatic output
Amino acids	Increased hepatic uptake for gluconeogenesis
Urea	Increased production
Fatty acids	Increased oxidation
Ketones	Increased production