Glucagon
glucagon (human, recombinant), GCG gene product, proglucagon (33-61), glucagon hydrochloride, nasal glucagon
Glucagon is the 29-amino-acid counter-regulatory hormone secreted by pancreatic alpha cells, and simultaneously a licensed medicine. As a drug it is used to reverse severe hypoglycaemia, as a diagnostic aid to relax gastrointestinal smooth muscle during imaging, and off-label as an antidote in beta-blocker and calcium-channel-blocker poisoning. It is the physiological counterpart of insulin and the parent molecule for the glucagon receptor arm of every dual and triple incretin agonist now in development.
Mechanism
Glucagon is encoded by GCG (UniProt P01275), which produces preproglucagon, a precursor processed in a tissue-specific manner. In pancreatic alpha cells, prohormone convertase 2 liberates glucagon itself; in intestinal L cells and in the brain, prohormone convertase 1/3 cleaves the same precursor to yield GLP-1, GLP-2 and oxyntomodulin. This shared origin explains why glucagon, GLP-1 and oxyntomodulin have overlapping sequences and cross-reacting receptors, and is the structural basis for the entire multi-agonist drug class.
Glucagon acts on the glucagon receptor, a class B1 G-protein-coupled receptor expressed most densely on hepatocytes. Gs coupling raises cyclic AMP and activates protein kinase A, which phosphorylates phosphorylase kinase to drive glycogenolysis and inactivates glycogen synthase to halt glycogen storage. Over a longer timescale, CREB and PGC-1alpha signalling induces the gluconeogenic programme through PEPCK and glucose-6-phosphatase, and hepatic fatty acid oxidation and ureagenesis are stimulated. Secondary Gq coupling raises intracellular calcium. Outside the liver, glucagon relaxes gastrointestinal smooth muscle, which is the basis of its diagnostic indication, and exerts positive inotropic and chronotropic effects on the heart through cardiac cyclic AMP generation that bypasses the beta-adrenoceptor entirely, which is why it is used in beta-blocker overdose. Because the acute glucose-raising effect depends on mobilising stored hepatic glycogen, glucagon is largely ineffective when those stores are depleted, as in prolonged starvation, chronic alcohol misuse, adrenal insufficiency or repeated recent hypoglycaemia.
What the research shows
Injectable glucagon for severe hypoglycaemia predates the modern randomised trial era and was licensed on the strength of its physiology and observational use rather than placebo-controlled trials, which would be ethically impossible. The modern randomised evidence concerns route of administration. Rickels and colleagues conducted a randomised crossover non-inferiority study in 75 adults with type 1 diabetes across eight centres, comparing 3 mg nasal glucagon with 1 mg intramuscular glucagon during insulin-induced hypoglycaemia. Treatment success was achieved in 98.7% of nasal administrations and 100% of intramuscular ones, with mean times to success of 16 and 13 minutes respectively; head or facial discomfort was reported at 25% of nasal versus 9% of intramuscular dosing visits. A Japanese phase 3 crossover study by Matsuhisa and colleagues replicated the efficacy finding in type 1 and type 2 diabetes.
Two practical findings deserve mention. Guzman and colleagues showed that nasal glucagon absorption is preserved during the common cold and in the presence of a nasal decongestant, addressing a plausible objection to intranasal delivery. Suico and colleagues compared nasal and intramuscular routes directly in 66 adults with type 1 diabetes and confirmed comparable glycaemic recovery. Collectively these establish that the nasal route is a practical substitute for injection, which matters because reconstitution of lyophilised glucagon by a frightened bystander is a well-documented point of failure in real emergencies. The evidence does not support glucagon as a treatment for anything chronic, and glucagon's therapeutic interest in metabolic disease now lies almost entirely in receptor agonism as a component of engineered dual and triple agonists rather than in the native hormone.
Evidence assessment
High-quality evidence
Glucagon holds approved labelling in the United States, United Kingdom and European Union for severe hypoglycaemia and as a diagnostic aid, backed by decades of clinical use and by modern randomised crossover trials comparing nasal against intramuscular administration in insulin-induced hypoglycaemia. All four cited studies were individually verified. Note that the strong tier applies to these specific licensed uses; glucagon's role as a chronic metabolic therapy is not established and is not what it is licensed for.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Intranasal Glucagon for Treatment of Insulin-Induced Hypoglycemia in Adults With Type 1 Diabetes: A Randomized Crossover Noninferiority Study Preclinical only
Treatment success occurred in 98.7% of nasal administrations versus 100% of intramuscular, with mean times to success of 16 and 13 minutes. Head or facial discomfort was reported at 25% of nasal versus 9% of intramuscular dosing visits. Nasal glucagon met the non-inferiority criterion.
Glucagon Administration by Nasal and Intramuscular Routes in Adults With Type 1 Diabetes During Insulin-Induced Hypoglycaemia: A Randomised, Open-Label, Crossover Study Preclinical only
Nasal and intramuscular glucagon produced comparable glycaemic recovery from insulin-induced hypoglycaemia, supporting interchangeability of routes in an emergency.
Nasal glucagon as a viable alternative for treating insulin-induced hypoglycaemia in Japanese patients with type 1 or type 2 diabetes: A phase 3 randomized crossover study Preclinical only
Nasal glucagon reversed insulin-induced hypoglycaemia comparably to intramuscular glucagon, replicating the Western findings in a Japanese population.
Effects of common cold and concomitant administration of nasal decongestant on the pharmacokinetics and pharmacodynamics of nasal glucagon in otherwise healthy participants: A randomized clinical trial Preclinical only
Nasal congestion, with or without a decongestant, did not meaningfully impair glucagon absorption or the glucose response, addressing a practical objection to the intranasal route.
Safety
Nausea and vomiting are the dominant adverse effects and are common at therapeutic doses, which is a practical hazard in a person recovering consciousness after hypoglycaemia. Nasal formulations add nasal and ocular discomfort, lacrimation, rhinorrhoea, nasal congestion and headache; head or facial discomfort was reported at a quarter of nasal dosing visits in the pivotal crossover trial. Rebound hyperglycaemia follows glycogenolysis and may require monitoring. Glucagon is contraindicated in phaeochromocytoma, where it can provoke catecholamine release and hypertensive crisis, and it is used with great caution in insulinoma and glucagonoma. It is ineffective in the absence of hepatic glycogen, so it should not be relied upon in prolonged fasting, chronic alcohol misuse, adrenal insufficiency or after repeated recent hypoglycaemic episodes, where intravenous glucose is required instead. Diagnostic doses can cause hypokalaemia. Hypersensitivity reactions, including rare anaphylaxis, have been reported. It transiently antagonises the effect of warfarin and can potentiate anticoagulation.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Authorised by the MHRA (with prior EU-wide authorisation) for the treatment of severe hypoglycaemia in adults and children and as a diagnostic aid to reduce gastrointestinal motility. Nasal glucagon was authorised in the European Union in December 2019 for use from four years of age. Prescription-only medicine; not a controlled drug. Glucagon appears on the WHO Model List of Essential Medicines and injection kits are routinely supplied to people at risk of severe hypoglycaemia. |
| United States | FDA-approved. Injectable glucagon is licensed for the treatment of severe hypoglycaemia in people with diabetes and as a diagnostic aid to inhibit gastrointestinal motility during radiological or endoscopic examination. Recombinant human glucagon has replaced animal-sourced material. A nasal glucagon dry powder was approved in July 2019, and ready-to-use liquid injection and autoinjector presentations followed. Prescription-only. Dasiglucagon, a stabilised analogue, is a separate compound and is not glucagon. |
| WADA (sport) | Not prohibited. Glucagon does not appear on the WADA Prohibited List. This is a notable asymmetry with its physiological counterpart insulin, which is prohibited at all times under section S4. There is no evidence that glucagon confers a performance advantage, and its minutes-long half-life makes any such use impractical. |
Questions
Yes. It is a single-chain peptide of 29 amino acids with no disulfide bonds, made from the same preproglucagon precursor that yields GLP-1, GLP-2 and oxyntomodulin. That shared parentage is why glucagon-based drug design overlaps so heavily with GLP-1 drug design.
Because it works by releasing stored liver glycogen. If those stores are depleted, as in prolonged fasting, chronic alcohol misuse, adrenal insufficiency or after repeated recent hypoglycaemia, there is nothing to mobilise. Intravenous glucose is then the only reliable treatment.
Glucagon receptor activation genuinely increases hepatic fatty acid oxidation and energy expenditure, which is why it is being built into dual and triple agonist drugs. But native glucagon has a half-life of minutes and raises blood glucose sharply, so it is useless as a fat-loss agent in its own right and is not licensed for anything of the sort.
Because it raises cardiac cyclic AMP through its own receptor, bypassing the blocked beta-adrenoceptor entirely, and so restores contractility and heart rate when adrenergic agents cannot. This is an established off-label use rather than a licensed indication in most jurisdictions.