Glucagon Peptide: Complete Profile

Glucagon is the metabolic counterweight to insulin. While insulin lowers blood glucose, glucagon raises it. This 29-amino-acid peptide hormone, secreted by pancreatic alpha cells, maintains blood sugar stability between meals and prevents dangerous hypoglycemia. Clinically, it's the first-line rescue therapy for severe low blood sugar episodes in people with diabetes. But glucagon's reach extends beyond emergency treatment. It's now a key component in next-generation obesity drugs, where activating the glucagon receptor alongside GLP-1 and GIP receptors produces weight loss that single-hormone therapies cannot match.

This profile covers glucagon's structure, mechanisms, clinical applications, connection to the proglucagon peptide family, role in dual and triple agonist research, and safety considerations.

Quick Facts
What Is Glucagon?
How Glucagon Works
Clinical Uses
The Proglucagon Connection
Glucagon in Next-Generation Metabolic Drugs
Safety and Side Effects
Frequently Asked Questions
Bottom Line
References

Quick Facts

Attribute	Details
Full Name	Glucagon
Type	Pancreatic peptide hormone
Amino Acids	29
Molecular Weight	3,483 Da
Precursor	Proglucagon (tissue-specific processing)
Primary Source	Pancreatic alpha cells
Receptor	Glucagon receptor (GCGR), a class B G-protein coupled receptor
Primary Function	Raises blood glucose via hepatic glycogenolysis and gluconeogenesis
FDA-Approved Uses	Severe hypoglycemia treatment; diagnostic aid in gastrointestinal imaging
Brand Names	GlucaGen, Baqsimi (nasal), Gvoke (auto-injector)
Legal Status	Prescription medication (United States)

What Is Glucagon?

Glucagon is a 29-amino-acid single-chain polypeptide hormone produced predominantly by alpha (α) cells in the pancreatic islets of Langerhans. Its amino acid sequence is: His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr.

Glucagon's primary physiological role is counter-regulation of insulin. When blood glucose drops—between meals, during fasting, or overnight—alpha cells release glucagon to restore glucose levels. This prevents hypoglycemia and maintains fuel supply to the brain and other glucose-dependent tissues.

Glucagon belongs to a family of structurally related peptides derived from the proglucagon precursor. These include GLP-1 (glucagon-like peptide-1), GLP-2, oxyntomodulin, and glicentin. Despite their shared origin, these peptides have distinct functions based on where and how proglucagon is processed.

How Glucagon Works

Glucagon raises blood glucose through three main mechanisms: glycogenolysis, gluconeogenesis, and lipolysis.

Mechanism 1: Glycogenolysis

Glucagon binds to glucagon receptors (GCGR) on hepatocytes (liver cells). This activates a G-protein signaling cascade that increases cyclic AMP (cAMP) levels inside the cell. Elevated cAMP activates protein kinase A, which then phosphorylates and activates enzymes that break down glycogen—the liver's stored form of glucose—into individual glucose molecules. These glucose molecules are released into the bloodstream, raising blood sugar within minutes.

This mechanism works only when liver glycogen stores are adequate. In prolonged fasting, starvation, or chronic alcohol use, glycogen stores are depleted, and glucagon's glucose-raising effect is diminished.

Mechanism 2: Gluconeogenesis

When glycogen stores run low, glucagon shifts the liver into glucose production mode. It stimulates gluconeogenesis—the synthesis of new glucose from non-carbohydrate precursors like amino acids (from protein breakdown), lactate, and glycerol (from fat breakdown). Glucagon turns off glycolysis (glucose breakdown) in hepatocytes, rerouting metabolic intermediates toward glucose synthesis instead. This maintains blood glucose during extended periods without food.

Mechanism 3: Lipolysis and Fatty Acid Mobilization

Glucagon promotes the breakdown of fat stores in adipose tissue and the liver. It decreases fatty acid synthesis and increases lipolysis, releasing fatty acids into circulation. These fatty acids serve as an alternative fuel source for skeletal muscle and other tissues, sparing glucose for the brain. This process also reduces hepatic lipogenesis, which may contribute to glucagon's potential role in treating metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD).

Receptor and Signaling Pathway

The glucagon receptor (GCGR) is a class B G-protein coupled receptor. When glucagon binds, the receptor undergoes a conformational change that activates a heterotrimeric G protein with αs, β, and γ subunits. This triggers adenylyl cyclase, which converts ATP to cAMP, initiating downstream signaling cascades that regulate glucose and lipid metabolism.

Glucagon's effects are most pronounced in the liver, where GCGR expression is highest. However, glucagon also acts on adipose tissue, kidneys, and the gastrointestinal tract.

Clinical Uses

Glucagon has two FDA-approved indications: treatment of severe hypoglycemia and use as a diagnostic aid in gastrointestinal imaging.

Severe Hypoglycemia

Glucagon is the first-line emergency treatment for severe hypoglycemia in people with diabetes who are unconscious or unable to consume oral carbohydrates. Hypoglycemia occurs when blood glucose drops too low—typically below 70 mg/dL—and can lead to confusion, seizures, loss of consciousness, and, if untreated, death.

Glucagon works by mobilizing glucose from the liver, rapidly raising blood sugar. An unconscious person with hypoglycemia usually regains consciousness within 15 minutes of receiving glucagon. If there is no response after 15 minutes, a second dose may be given while waiting for emergency medical services.

Available Formulations

Multiple glucagon formulations are FDA-approved for treating severe hypoglycemia:

GlucaGen HypoKit (Novo Nordisk): Approved in 1998, this is a traditional glucagon emergency kit that requires reconstitution (mixing powder with liquid) before injection. It can be administered intramuscularly, subcutaneously, or intravenously.
Gvoke (Xeris Pharmaceuticals): Approved in 2019, Gvoke is a ready-to-use liquid glucagon formulation available as a prefilled syringe (Gvoke PFS) or auto-injector (Gvoke HypoPen). It eliminates the reconstitution step, making administration faster and simpler during emergencies. Clinical trials showed 100% treatment success in children and 99% in adults with type 1 diabetes.
Baqsimi (Eli Lilly): Approved in 2019, Baqsimi is the first and only nasal powder formulation of glucagon. It delivers a 3 mg dose via a single-use nasal device that does not require inhalation to work. It is effective even if the person has a cold or is taking cold medications. Clinical trials demonstrated comparable efficacy to injectable glucagon.

These formulations improve accessibility and ease of use, particularly for caregivers and family members who may be unfamiliar with injections or medical procedures.

Diagnostic Imaging

Glucagon is approved as a diagnostic aid for temporarily relaxing smooth muscle in the gastrointestinal tract during radiologic examinations. It induces hypotonia (reduced muscle tone) in the stomach, small intestine, and colon, allowing clearer visualization during procedures like MRI, CT scans, and X-rays. This helps clinicians distinguish between functional and structural abnormalities, assess organ elasticity, and evaluate stenoses or enlarged folds.

Glucagon is also used during endoscopic procedures, biopsies, abscess drainage, GI stenting, and gastrostomy tube placement. It replaced anticholinergic agents in the 1970s due to its safer side effect profile and more predictable duration of action.

Off-Label Uses

Glucagon has several off-label applications, including:

Beta-blocker overdose: Glucagon can counteract the cardiac effects of beta-blocker toxicity by increasing heart rate and contractility independent of beta-adrenergic receptors.
Calcium channel blocker overdose: As adjunctive therapy, glucagon may improve cardiac output.
Esophageal food impaction: Glucagon relaxes the lower esophageal sphincter, potentially allowing impacted food to pass.

The Proglucagon Connection

Glucagon, GLP-1, and GLP-2 all originate from the same gene: the proglucagon gene (Gcg). But they are not identical. Proglucagon is a large precursor protein that gets cleaved into different peptides depending on the tissue and the enzymes present.

Tissue-Specific Processing

In pancreatic alpha cells, the enzyme prohormone convertase 2 (PC2) cleaves proglucagon into:

Glicentin-related pancreatic peptide (GRPP)
Glucagon (the subject of this profile)
Intervening peptide-1 (IP-1)
Major proglucagon fragment (MPGF)

In intestinal L-cells and certain brain neurons, prohormone convertase 1/3 (PC1/3) cleaves proglucagon into:

Glicentin (which can be further processed into GRPP and oxyntomodulin)
GLP-1 (glucagon-like peptide-1)
Intervening peptide-2 (IP-2)
GLP-2 (glucagon-like peptide-2)

This differential processing explains why the same gene produces peptides with opposing or complementary metabolic functions. Glucagon raises blood sugar. GLP-1 enhances insulin secretion and inhibits glucagon release. Both play critical roles in glucose homeostasis, but from different anatomical and functional perspectives.

Structural Homology

Glucagon shares structural similarity with secretin, vasoactive intestinal polypeptide (VIP), and gastric inhibitory polypeptide (GIP). All belong to the glucagon superfamily of peptide hormones. Their receptors—GCGR, GLP-1R, GLP-2R, GIPR—are all class B GPCRs, which is why cross-receptor activity is possible and why dual and triple agonists are pharmacologically feasible.

Cross-Receptor Activity

The glucagon receptor and GLP-1 receptor can bind each other's ligands, though with lower affinity. The GLP-1 receptor binds both GLP-1 and glucagon as endogenous agonists, and the glucagon receptor can respond to GLP-1 at supraphysiological concentrations. This cross-reactivity has therapeutic implications, particularly in the development of dual and triple agonist drugs.

Glucagon in Next-Generation Metabolic Drugs

For decades, glucagon was viewed primarily as a problem in diabetes—elevated glucagon contributes to hyperglycemia in type 1 and type 2 diabetes. But recent research has reframed glucagon as a therapeutic target for obesity and metabolic disease when combined with GLP-1 and GIP receptor activation.

Dual Agonists: GLP-1/Glucagon

Drugs that activate both the GLP-1 receptor and the glucagon receptor produce greater weight loss than GLP-1 agonists alone. The mechanism involves:

GLP-1 activity: Reduces appetite, slows gastric emptying, enhances insulin secretion, inhibits glucagon release.
Glucagon activity: Increases energy expenditure, promotes hepatic fatty acid oxidation, reduces hepatic lipogenesis, and may improve liver fat metabolism.

The combination produces additive or synergistic effects on weight loss and metabolic health.

Survodutide

Survodutide is a GLP-1/glucagon dual agonist currently in phase 3 clinical trials. In phase 2 studies in people with metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis, survodutide significantly improved liver steatosis (fat accumulation) and led to histologic improvement of MASH without worsening fibrosis in 43–62% of participants, compared to 14% with placebo. It also produced meaningful weight loss.

Survodutide's glucagon activity stimulates hepatic fatty acid oxidation, which helps clear fat from the liver—a mechanism not available with GLP-1-only agonists.

Mazdutide

Mazdutide is another GLP-1/glucagon dual agonist in clinical development. It targets both weight loss and metabolic improvements through combined receptor activation.

Triple Agonists: GLP-1/GIP/Glucagon

Triple agonists activate the GLP-1 receptor, GIP receptor, and glucagon receptor simultaneously. Preclinical studies in rodents show that triple agonists produce greater weight loss than mono-agonists or dual agonists.

Retatrutide

Retatrutide is the first GLP-1/GIP/glucagon triple agonist to complete phase 2 trials. It has shown remarkable efficacy:

Weight loss: Mean weight loss of up to 24.2% after 48 weeks in people with obesity, and 16.9% after 36 weeks in people with type 2 diabetes.
Metabolic improvements: Significant reductions in body mass index (−5.38), waist circumference (−10.51 cm), fasting plasma glucose (−23.51 mg/dL), and hemoglobin A1c (−0.91%).
Prediabetes reversal: 72% of participants with prediabetes at baseline reverted to normoglycemia.

Retatrutide is more potent at the human GIP receptor (EC50: 0.0643 nM) than at the GLP-1 receptor (EC50: 0.775 nM) or glucagon receptor (EC50: 5.79 nM). Phase 3 trials are underway.

Why Glucagon Activity Matters in Obesity Treatment

Glucagon's contribution to weight loss in dual and triple agonists is multifactorial:

Increased energy expenditure: Glucagon stimulates thermogenesis and metabolic rate.
Hepatic fat oxidation: Promotes breakdown of liver fat, improving MASLD/MASH.
Reduced hepatic lipogenesis: Decreases new fat synthesis in the liver.
Muscle energy use: Shifts metabolism toward fatty acid oxidation in skeletal muscle.

This makes glucagon receptor activation a critical component of next-generation obesity pharmacotherapy, particularly when paired with GLP-1's appetite-suppressing and insulin-enhancing effects.

Safety and Side Effects

Glucagon is generally well-tolerated when used as prescribed for hypoglycemia or diagnostic imaging. However, side effects and contraindications exist.

Common Side Effects

Nausea: The most frequently reported side effect, with an incidence reaching up to 35% in some studies.
Vomiting: Often accompanies nausea, particularly at higher doses.
Headache: Reported in a subset of patients.
Injection site reactions: Pain, swelling, or redness may occur with injectable formulations.
Nasal and ocular symptoms: With Baqsimi nasal powder, users may experience upper respiratory tract irritation, watery eyes, redness, itchy nose, throat, and eyes.

Serious Side Effects

Allergic reactions: Rare but can be serious. Symptoms include rash, difficulty breathing, and swelling of the face or throat.
Hypertension: Increased blood pressure, particularly in patients with pheochromocytoma.
Hypotension: Low blood pressure may occur in some individuals.
Hypokalemia: Low blood potassium levels.

Contraindications

Glucagon should not be used in the following conditions:

Pheochromocytoma: A tumor of the adrenal gland that can cause dangerously high blood pressure when exposed to glucagon.
Insulinoma: A pancreatic tumor that secretes excess insulin. Glucagon can trigger rebound hypoglycemia in these patients.
Glucagonoma: A rare pancreatic tumor that secretes excess glucagon.
Known hypersensitivity: Allergy to glucagon, lactose, or any excipients in the formulation.

Limitations

Glucagon requires adequate liver glycogen stores to work. It is less effective or ineffective in:

Prolonged fasting or starvation: Glycogen stores are depleted.
Adrenal insufficiency: Impaired glucose production.
Chronic alcohol use: Depleted hepatic glycogen.

In these situations, intravenous dextrose is the preferred treatment for hypoglycemia.

Use in Special Populations

Pregnancy: Glucagon has not been found to harm the developing fetus, but it should be used only when clearly needed.
Pediatrics: Glucagon is safe and effective for treating severe hypoglycemia in children aged 1 year and older (depending on formulation).
Geriatrics: No specific dosage adjustments are required, but older adults may be more sensitive to side effects.

Frequently Asked Questions

Is glucagon the same as GLP-1?

No. Glucagon and GLP-1 are both derived from the same proglucagon precursor, but they are processed in different tissues and have different functions. Glucagon is produced in pancreatic alpha cells and raises blood glucose. GLP-1 is produced in intestinal L-cells and enhances insulin secretion while inhibiting glucagon release. Despite their shared origin, they act on different receptors (GCGR vs. GLP-1R) and have complementary roles in metabolism.

Can glucagon cause weight loss?

Not when used alone at therapeutic doses for hypoglycemia. However, when combined with GLP-1 and/or GIP receptor agonists in dual or triple agonist drugs like survodutide or retatrutide, glucagon receptor activation contributes to greater weight loss by increasing energy expenditure and promoting fat oxidation.

How quickly does glucagon work for hypoglycemia?

Glucagon typically raises blood glucose within 10 to 15 minutes when administered intramuscularly or subcutaneously. Nasal glucagon (Baqsimi) has a similar onset of action. Intravenous glucagon works even faster. An unconscious person usually regains consciousness within 15 minutes. If there is no response after 15 minutes, a second dose may be administered, and emergency medical services should be contacted.

Is glucagon safe for children?

Yes. Glucagon is FDA-approved for treating severe hypoglycemia in children with diabetes. Baqsimi is approved for ages 4 and above, though some formulations are approved for children as young as 1 year. Dosage may vary based on the child's weight and the specific product used.

Can glucagon be used if someone has been drinking alcohol?

Glucagon may be less effective in people who have consumed large amounts of alcohol, as alcohol depletes liver glycogen stores. However, it should still be administered in cases of severe hypoglycemia while emergency medical help is sought. Intravenous dextrose may be needed if glucagon does not restore consciousness.

What is the difference between GlucaGen, Gvoke, and Baqsimi?

All three are FDA-approved glucagon formulations for treating severe hypoglycemia, but they differ in delivery method:

GlucaGen HypoKit: Requires reconstitution (mixing powder and liquid) before injection. Can be given intramuscularly, subcutaneously, or intravenously.
Gvoke: A ready-to-use liquid formulation available as a prefilled syringe or auto-injector. No reconstitution required.
Baqsimi: A nasal powder that delivers glucagon via a single-use nasal device. Does not require injection or inhalation.

All are effective, but Gvoke and Baqsimi are easier to use in emergencies due to simplified administration.

Can glucagon be used for conditions other than hypoglycemia?

Yes. Glucagon is FDA-approved as a diagnostic aid in gastrointestinal imaging to temporarily relax smooth muscle in the GI tract. It also has off-label uses, including treatment of beta-blocker overdose, calcium channel blocker overdose, and esophageal food impaction.

Why is glucagon being studied for obesity if it raises blood sugar?

In the context of dual and triple agonist drugs, glucagon receptor activation is paired with GLP-1 and/or GIP receptor activation. The combination produces metabolic effects that are different from glucagon alone. While glucagon can raise blood glucose acutely, its effects on energy expenditure, fat oxidation, and hepatic metabolism—when combined with GLP-1's insulin-enhancing and appetite-suppressing effects—result in net weight loss and improved glycemic control in obesity and type 2 diabetes.

Bottom Line

Glucagon is the metabolic counterbalance to insulin. This 29-amino-acid pancreatic hormone raises blood glucose when it drops too low, preventing hypoglycemia and maintaining fuel supply to the brain. Clinically, it is the first-line emergency treatment for severe hypoglycemia in people with diabetes, available in injectable and nasal formulations that have made administration faster and simpler.

But glucagon's role extends beyond emergency rescue. It is a member of the proglucagon peptide family, sharing a genetic origin with GLP-1 and GLP-2, yet serving distinct physiological functions. And in recent years, glucagon has become a key player in next-generation metabolic therapies. Dual agonists like survodutide and triple agonists like retatrutide combine glucagon receptor activation with GLP-1 and GIP signaling to produce weight loss and metabolic improvements that single-hormone therapies cannot achieve.

For anyone interested in peptide therapeutics, understanding glucagon is foundational. It is both a clinical tool and a building block for the next wave of obesity and diabetes treatments.

Disclaimer: This article is for educational purposes only and does not constitute medical advice. PeptideJournal.org does not sell peptides or provide medical services. Glucagon is a prescription medication. Anyone experiencing severe hypoglycemia should seek emergency medical care. For information about specific medical conditions or treatments, consult a licensed healthcare provider.

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