Glucagon

Glucagon is a peptide hormone produced by the alpha cells of the pancreatic islets that plays a critical role in glucose homeostasis by raising blood sugar levels when they fall too low. Its primary human-use benefits include emergency treatment of severe hypoglycemia, diagnostic testing of gastrointestinal function, and emerging applications in metabolic research. Glucagon is popular among diabetics using insulin therapy, emergency medical personnel, and researchers investigating metabolic disorders. Standard emergency doses range from 0.5 mg to 1 mg administered intramuscularly, subcutaneously, or intranasally, with blood glucose elevation typically occurring within 10-20 minutes of administration.

What Is Glucagon?

Glucagon is a 29-amino acid peptide hormone secreted by the alpha cells of the islets of Langerhans in the pancreas. It functions as the primary counter-regulatory hormone to insulin, working to prevent hypoglycemia by stimulating hepatic glucose production.

Definition

Structurally, glucagon belongs to the secretin family of peptide hormones. It is synthesized as part of a larger precursor molecule called proglucagon, which is processed differently in various tissues to yield glucagon in the pancreas and glucagon-like peptides (GLP-1 and GLP-2) in the intestines and brain.

Why It's Popular and Unique

Glucagon occupies a unique position in metabolic medicine as the only hormone approved specifically for raising blood glucose levels. Unlike other hyperglycemic agents, glucagon works rapidly and reliably through direct hepatic action. Its life-saving potential in hypoglycemic emergencies has made it an essential component of diabetes management kits worldwide. Recent pharmaceutical innovations have expanded delivery options beyond traditional injection to include nasal sprays and auto-injectors, dramatically improving accessibility and ease of use.

Primary Human-Use Benefits

The established benefits of glucagon include:

• Rapid reversal of severe hypoglycemia in diabetic patients
• Diagnostic aid for radiological examination of the gastrointestinal tract by inducing smooth muscle relaxation
• Beta-blocker and calcium channel blocker overdose treatment
• Potential applications in weight management when combined with GLP-1 agonists (dual and triple agonist formulations)
• Investigational use in closed-loop artificial pancreas systems

How It Works

Receptor Binding and Signal Transduction

Glucagon exerts its effects by binding to the glucagon receptor (GCGR), a G protein-coupled receptor predominantly expressed in the liver. Upon binding, the receptor activates adenylyl cyclase through stimulatory G proteins (Gs), leading to increased intracellular cyclic adenosine monophosphate (cAMP) concentrations. This second messenger cascade activates protein kinase A (PKA), which phosphorylates key enzymes involved in glucose metabolism.

Hepatic Glycogenolysis

The most immediate effect of glucagon is the stimulation of glycogenolysis—the breakdown of glycogen stores into glucose. PKA phosphorylates and activates glycogen phosphorylase kinase, which in turn activates glycogen phosphorylase. Simultaneously, PKA inhibits glycogen synthase, preventing glucose from being stored as glycogen. This dual action rapidly mobilizes hepatic glucose reserves, typically raising blood glucose within 10-15 minutes.

Gluconeogenesis Stimulation

Beyond glycogenolysis, glucagon promotes gluconeogenesis—the synthesis of new glucose molecules from non-carbohydrate precursors including lactate, amino acids, and glycerol. This process involves upregulation of key enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase through cAMP response element-binding protein (CREB) activation. Gluconeogenesis provides sustained glucose production when glycogen stores become depleted.

Lipolysis and Ketogenesis

Glucagon also promotes lipolysis in adipose tissue, releasing free fatty acids that can be oxidized for energy or converted to ketone bodies in the liver. This metabolic shift becomes particularly important during prolonged fasting or when glucose availability is limited. The ketogenic effect of glucagon provides alternative fuel substrates for tissues, including the brain during extended hypoglycemia.

Dosage Protocols

Emergency Hypoglycemia Treatment

For severe hypoglycemia in adults and children weighing more than 25 kg (55 lbs), the standard dose is 1 mg (1 unit) administered intramuscularly, subcutaneously, or intranasally. Children weighing less than 25 kg should receive 0.5 mg (0.5 units). The dose may be repeated after 15 minutes if the patient does not respond adequately.

Diagnostic Procedures

For gastrointestinal radiological examinations, doses vary by procedure:

• Stomach, duodenum, and small bowel relaxation: 0.25-0.5 mg IV or 1-2 mg IM
• Colon relaxation: 0.5-0.75 mg IV or 1-2 mg IM

The IV route provides faster onset (1 minute) but shorter duration (9-17 minutes), while IM administration has slower onset (8-10 minutes) but longer duration (12-27 minutes).

Beta-Blocker Overdose

In cases of beta-blocker toxicity, initial bolus doses of 3-10 mg IV are administered, followed by continuous infusion of 3-5 mg/hour as needed. This off-label use requires careful monitoring in a clinical setting.

How to Use / Administration Methods

Injectable Formulations

Traditional glucagon emergency kits require reconstitution before injection. The lyophilized powder must be mixed with the provided diluent immediately before use. Injection sites include the upper arm, thigh, or buttocks for intramuscular administration, or the abdomen or thigh for subcutaneous injection.

Nasal Administration

Nasal glucagon (Baqsimi) delivers 3 mg of glucagon powder intranasally without reconstitution. The device is inserted into one nostril and the plunger is pushed until the green line disappears. Absorption occurs through the nasal mucosa regardless of whether the patient inhales or is congested.

Auto-Injector Systems

Pre-mixed, ready-to-use glucagon auto-injectors (Gvoke) eliminate reconstitution requirements. These devices deliver 0.5 mg or 1 mg doses subcutaneously or intramuscularly with simple push-button activation.

Results Timelines

Blood glucose elevation typically begins within 10 minutes of intramuscular or subcutaneous injection, with peak effects occurring at 20-30 minutes. Intravenous administration produces faster onset (1-2 minutes) with peak effects at 5-15 minutes. Nasal glucagon demonstrates comparable efficacy to injectable forms, with meaningful glucose elevation within 15-20 minutes.

The duration of hyperglycemic effect ranges from 60-90 minutes depending on the route of administration and individual glycogen stores. Patients with depleted hepatic glycogen (due to prolonged fasting, adrenal insufficiency, or chronic hypoglycemia) may show diminished response.

Research Evidence

Clinical trials have consistently demonstrated glucagon's efficacy in treating severe hypoglycemia. A pivotal study comparing nasal glucagon to intramuscular glucagon in adults with type 1 diabetes showed that 100% of patients achieved treatment success (blood glucose ≥70 mg/dL or increase ≥20 mg/dL within 30 minutes) with both formulations.

Research into dual glucagon/GLP-1 receptor agonists has shown promising results for obesity and type 2 diabetes treatment. These compounds leverage glucagon's energy expenditure-increasing properties while counterbalancing its hyperglycemic effects with GLP-1's insulin-stimulating action.

Ongoing investigations into artificial pancreas systems incorporate glucagon as a counter-regulatory component to prevent hypoglycemia during automated insulin delivery. Bihormonal closed-loop systems using both insulin and glucagon have demonstrated improved glycemic control compared to insulin-only systems in clinical trials.

Stacking

Glucagon is not typically "stacked" in the traditional sense used for performance-enhancing peptides. However, its combination with other hormones has therapeutic applications:

In bihormonal artificial pancreas systems, glucagon works alongside rapid-acting insulin to maintain euglycemia. The insulin component lowers elevated blood glucose while mini-doses of glucagon prevent or treat impending hypoglycemia.

Investigational dual agonists combining glucagon receptor activation with GLP-1 receptor agonism (such as cotadutide and survodutide) represent a pharmacological approach to metabolic disease that leverages the complementary actions of both hormones.

Reconstitution, Storage & Preparation

Traditional Kits

Lyophilized glucagon powder should be stored at controlled room temperature (20-25°C/68-77°F) before reconstitution. To prepare, inject the entire contents of the diluent syringe into the vial containing the powder, then gently swirl until completely dissolved. The solution should be clear and colorless; do not use if cloudy or discolored.

Reconstituted glucagon must be used immediately and cannot be stored. Any unused portion should be discarded.

Stable Formulations

Ready-to-use glucagon products (Gvoke, Baqsimi) offer significant storage advantages. Gvoke auto-injectors and pre-filled syringes can be stored at room temperature (20-25°C) for up to 24 months. Baqsimi nasal powder should be stored at temperatures up to 30°C (86°F) and kept in the shrink-wrapped tube until use.

All glucagon products should be protected from light and kept in their original packaging until needed.

Side Effects

Common adverse effects of glucagon include:

• Nausea and vomiting (most frequent, occurring in up to 30% of patients)
• Headache
• Injection site reactions (pain, erythema, swelling)
• Transient hypertension and tachycardia
• Hypokalemia

Serious but rare adverse effects include:

• Allergic reactions (urticaria, respiratory distress, hypotension)
• Necrolytic migratory erythema (with prolonged exposure to elevated glucagon levels)
• Paradoxical hypoglycemia in patients with insulinoma

Glucagon is contraindicated in patients with pheochromocytoma due to the risk of catecholamine release and hypertensive crisis, and in patients with known hypersensitivity to glucagon or any product components.

Legal Status / FDA Approval

Glucagon is FDA-approved as a prescription medication for the treatment of severe hypoglycemia and as a diagnostic aid for radiological examination of the gastrointestinal tract. Multiple formulations have received approval:

• GlucaGen and Glucagon Emergency Kit (injectable): Long-established approval
• Baqsimi (nasal glucagon): Approved July 2019
• Gvoke (ready-to-use injectable): Approved September 2019
• Zegalogue (dasiglucagon): Approved March 2021

Glucagon is classified as a prescription-only medication in the United States, European Union, and most other jurisdictions. It is not a controlled substance.

Sports / WADA Status

Glucagon is included on the World Anti-Doping Agency (WADA) Prohibited List under category S4.5 (Metabolic Modulators) when used for performance-enhancing purposes. However, athletes with documented medical conditions requiring glucagon (such as type 1 diabetes) may apply for a Therapeutic Use Exemption (TUE) to use the hormone for legitimate medical treatment of hypoglycemia.

Conclusion

Glucagon remains an indispensable peptide hormone in emergency medicine and diabetes management. Its unique ability to rapidly elevate blood glucose levels makes it the definitive treatment for severe hypoglycemia—a potentially life-threatening condition affecting millions of insulin-treated diabetics worldwide. Recent innovations in delivery systems have transformed glucagon from a cumbersome emergency kit requiring reconstitution to user-friendly nasal sprays and auto-injectors that caregivers and patients can administer with minimal training.

Beyond its established emergency applications, glucagon continues to generate research interest in metabolic medicine. Dual and triple agonist formulations incorporating glucagon receptor activation represent promising therapeutic approaches for obesity and type 2 diabetes. As our understanding of glucagon's complex metabolic effects deepens, this essential peptide hormone will likely find expanded clinical applications in the years ahead.

Frequently Asked Questions

How quickly does glucagon work for hypoglycemia?
Glucagon typically raises blood glucose within 10-15 minutes when administered intramuscularly or subcutaneously, with peak effects at 20-30 minutes. Intravenous administration works faster, within 1-2 minutes.

Can glucagon be used if the patient is conscious?
Glucagon is primarily indicated for severe hypoglycemia when the patient cannot safely swallow oral glucose. Conscious patients who can swallow should receive fast-acting carbohydrates first.

Why does glucagon cause nausea?
Glucagon relaxes smooth muscle throughout the gastrointestinal tract, slowing gastric emptying and intestinal motility. This effect, combined with rapid metabolic changes, frequently causes nausea and vomiting.

Does glucagon work if someone hasn't eaten?
Glucagon's effectiveness depends on adequate hepatic glycogen stores. Patients who have been fasting for extended periods, are malnourished, or have adrenal insufficiency may have diminished response due to depleted glycogen.

How should expired glucagon be handled?
Expired glucagon should not be used except in life-threatening emergencies when no alternative is available. Dispose of expired products according to local pharmaceutical waste guidelines.

Can glucagon be self-administered?
While glucagon is typically administered by caregivers during hypoglycemic emergencies (when the patient is incapacitated), nasal glucagon and auto-injectors are designed for easier administration by trained family members or bystanders.

Is glucagon the same as glucose?
No. Glucagon is a hormone that signals the liver to release stored glucose. Glucose is the sugar molecule itself. Glucagon works indirectly by mobilizing the body's glucose reserves.

What happens if too much glucagon is given?
Glucagon overdose may cause persistent nausea, vomiting, hypokalemia, and transient hyperglycemia. Treatment is supportive, as glucagon has a short half-life (8-18 minutes) and effects resolve relatively quickly.

References

1. Glucagon - StatPearls - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK534787/
2. Glucagon Physiology - Endotext - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK279127/
3. Sandoval DA, D'Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev. 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988835/
4. FDA Approves First Treatment for Severe Hypoglycemia That Can Be Administered Without an Injection. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-severe-hypoglycemia-can-be-administered-without-injection
5. Glucagon receptor signaling and lipid metabolism. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812027/
6. Glucagon Dosage Guide - Drugs.com. https://www.drugs.com/dosage/glucagon.html
7. Nasal Glucagon for Hypoglycemia Treatment. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697189/
8. GLP-1/glucagon receptor co-agonism for treatment of obesity. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232639/
9. Bihormonal Closed-Loop Artificial Pancreas Systems. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478012/
10. WADA Prohibited List. https://www.wada-ama.org/en/prohibited-list