Where does glucagon (Glucagon) work?

Glucagon's Mechanism of Action and Site of Action

Glucagon primarily works by activating hepatic glucagon receptors in the liver, stimulating glycogen breakdown and glucose release, thereby increasing blood glucose concentration within 10 minutes of administration. 1

Primary Site of Action: The Liver

Glucagon's primary site of action is the liver, where it:

• Activates hepatic glucagon receptors 1
• Stimulates glycogen breakdown (glycogenolysis) 1
• Promotes release of glucose from the liver 1
• Increases hepatic glucose production during fasting and stress 2
• Requires adequate hepatic glycogen stores to be effective 1

The effectiveness of glucagon depends on having sufficient glycogen stores in the liver. This is an important clinical consideration, as patients with depleted glycogen stores (due to starvation, adrenal insufficiency, or chronic hypoglycemia) may have a diminished response to glucagon treatment 3.

Pharmacodynamics and Timing

When administered for severe hypoglycemia:

• Blood glucose begins to rise within 10 minutes of injection 1
• Peak blood glucose effect occurs at approximately 30 minutes 1
• The hyperglycemic action lasts 60-90 minutes after injection 1
• After subcutaneous administration of 1 mg, peak blood glucose averages 79.3 mg/dL at around 50 minutes 1

Secondary Sites of Action

Beyond the liver, glucagon has extrahepatic effects including:

• Relaxation of smooth muscle in the:
  • Stomach
  • Duodenum
  • Small bowel
  • Colon 1

Clinical Applications

Glucagon is indicated for the treatment of hypoglycemia in people unable or unwilling to consume carbohydrates by mouth 4. The American Diabetes Association recommends that:

• All individuals treated with insulin or at high risk of hypoglycemia should be prescribed glucagon 4
• Those in close contact with these individuals should be instructed on glucagon use 4
• Newer intranasal and ready-to-inject formulations are preferred due to ease of administration 4

Important Clinical Considerations

1. Liver Function: Patients with impaired liver function may have a diminished response to glucagon 3

2. Storage and Expiration: Care should be taken to replace glucagon products when they reach their expiration date and to store according to specific product instructions 4

3. Formulations: Multiple formulations are available including:

   • Traditional injection powder requiring reconstitution
   • Intranasal powder
   • Prefilled pens and syringes 4

4. Dosing: For most individuals with severe hypoglycemia, standard dosing applies, but those using automated insulin delivery systems may require adjusted protocols 4

Understanding glucagon's site of action in the liver is crucial for appropriate clinical use, particularly when treating severe hypoglycemia in diabetes patients.