Glucagon Function: What Glucagon Does and How It Works With Insulin

Glucagon function, in one sentence: glucagon is the pancreatic hormone that keeps blood glucose from falling too low, mainly by telling the liver to release stored glucose and make new glucose. That leaves out half the story. Glucagon also controls how the liver handles amino acids and fat, and its receptor is now a target in metabolic peptide research, from GLP-1/glucagon dual agonists to glucagon blockers that stalled in trials.

This guide covers where glucagon comes from, what its receptor does in the liver, what controls its secretion, glucagon vs insulin, what goes wrong in diabetes, and how researchers have tried both to block and to mimic it.

What is glucagon?

Glucagon is a peptide hormone: a single chain of 29 amino acids secreted by the alpha cells of the pancreatic islets, the small clusters of hormone-producing cells that also contain the insulin-secreting beta cells. Like insulin, it is one of the classic peptide hormones: it travels in the blood and acts through a receptor on its target cells, chiefly in the liver.

Textbooks call it insulin’s counter-regulatory partner, released when glucose runs low. That is accurate but incomplete. People with glucagon-secreting tumours carry a large excess of the hormone, yet their glucose metabolism is not necessarily disturbed; what stands out instead is accelerated amino-acid turnover and very low plasma amino acids.

From Toronto’s insulin to a second hormone

Glucagon was found because of insulin. Insulin was discovered in 1921 at the University of Toronto, work recognized by the 1923 Nobel Prize in Physiology or Medicine for Frederick Banting and John Macleod, and the need for cheap ways to extract safe insulin soon had laboratories elsewhere refining extraction methods. Our history of Canada’s century of peptide discovery tells that story.

While refining those methods, C. P. Kimball and John Murlin found a pancreatic substance that did the opposite of insulin, raising blood glucose in dogs and rabbits; they published in 1923 and named it glucagon. Its source was traced to the islet alpha cells in 1948; Bromer, Sinn and Behrens summarized the evidence for its full amino-acid sequence in 1957; and in 1961 Roger Unger’s group described the first sensitive radioimmunoassay, which made glucagon measurable in blood.

One precursor, several hormones

The GCG gene encodes a 180-residue precursor, preproglucagon, which loses a 20-residue signal peptide to become proglucagon. Proglucagon holds glucagon and two glucagon-like sequences, GLP-1 and GLP-2, and which hormones a cell releases depends on the enzyme that cuts it.

In pancreatic alpha cells that enzyme is prohormone convertase 2 (PC2), which yields mainly glucagon. In intestinal L cells it is prohormone convertase 1/3 (PC1/3). In 1996, Savita Dhanvantari and Patricia Brubaker of the University of Toronto, working with Nabil Seidah of the Clinical Research Institute of Montreal, expressed each candidate convertase in cell lines and found that PC1 generated the intestinal set: glicentin, oxyntomodulin, GLP-1 and GLP-2. One gene thus gives the pancreas a glucose-raising hormone and the gut the GLP-1 family covered in our GLP-1 research map.

Glucagon function in the liver: what glucagon does

The glucagon receptor

Glucagon acts through one receptor, the glucagon receptor (GCGR), a class B G-protein-coupled receptor whose human structure was published in 2013. Binding activates the G protein Gs; adenylate cyclase then makes cyclic AMP, which switches on protein kinase A (PKA) and, through it, the transcription factor CREB. Our guides to GPCRs and to cyclic AMP and protein kinase A explain the machinery. Receptor expression is highest in the liver.

Glucose: glycogen first, new glucose later

PKA activates phosphorylase kinase, which switches on glycogen breakdown and blocks glycogen synthesis within minutes. Over hours, CREB drives transcription of the gluconeogenic enzymes PEPCK and glucose-6-phosphatase. PKA also damps glycolysis, by lowering fructose-2,6-bisphosphate and phosphorylating pyruvate kinase, so the liver stops burning the glucose it exports. In a prolonged fast, as glycogen runs down, the glycogen route fades.

Amino acids and the liver–alpha-cell axis

Glucagon increases transcription of urea-cycle enzymes and amino-acid transporters, so the liver takes up more amino acids and converts their nitrogen to urea. In 2017, Holst and colleagues described the result as a complete feedback loop, the liver–alpha-cell axis: amino acids stimulate alpha cells, and glucagon clears amino acids. In glucagonoma, plasma amino acids fall and the characteristic rash, necrolytic migratory erythema, resolves with amino-acid infusion. Conversely, people with inactivating glucagon-receptor mutations, and receptor-knockout mice, can develop alpha-cell hyperplasia and excess glucagon secretion, which recent work links to the raised amino-acid levels that follow.

Fat, ketones and energy expenditure

In the liver, glucagon steers fatty acids toward oxidation: CREB raises expression of CPT-1, which carries fatty acids into mitochondria, and PKA inactivates acetyl-CoA carboxylase, lowering the malonyl-CoA that holds CPT-1 back. More oxidation means more ketone bodies and less triglyceride exported as VLDL. In human fat tissue its role is less clear: lipolysis through its receptor is shown in rat fat cells, but a receptor on human adipocytes has not been clearly demonstrated.

Glucagon also raises energy expenditure. In a 2016 study of 11 healthy men, a glucagon infusion raised it by about 15%, close to the 14% seen with cold exposure, without the neck-skin warming or noradrenaline rise that would point to brown adipose tissue thermogenesis.

What raises and lowers glucagon

Low glucose is the strongest stimulus, and glucose acts on alpha cells directly as well as through their neighbours. In a 2002 clamp study in healthy volunteers, glucagon rose at each hypoglycemic step tested: 3.7, 3.0 and 2.3 mmol/L.

GIP, amylin and somatostatin each have a dedicated guide.

Glucagon vs insulin

Glucagon and insulin are the two islet hormones that set blood glucose, and mostly they pull in opposite directions.

The last row is the one most summaries leave out. In perfused mouse pancreas, glucagon stimulated insulin secretion through both the GLP-1 receptor and the glucagon receptor on beta cells; removing either receptor alone changed little, but blocking both cut insulin secretion.

Glucagon in diabetes and in medicine

In 1970, Walter Müller, Roger Unger and colleagues gave carbohydrate and protein meals to 14 people without diabetes and 24 with it. Carbohydrate suppressed glucagon only in those without diabetes, and protein raised it in both groups; the authors concluded that inappropriate hyperglucagonemia is a common feature of human diabetes. In 1975, Unger and Lelio Orci argued in The Lancet for an essential role of glucagon in the disease, the root of a bihormonal view: too little insulin action plus too much glucagon action.

The strongest support comes from mice: glucagon-receptor knockout mice whose beta cells were destroyed did not become hyperglycemic or ketotic. In 2012, Unger and Alan Cherrington built a “glucagonocentric” view of diabetes on such findings, while noting that the knockout results came from mice and had yet to be shown in humans. Human data are less tidy: not everyone with type 2 diabetes has fasting hyperglucagonemia.

In 1973, John Gerich and colleagues found that glucagon did not rise in six people with juvenile-onset diabetes during insulin-induced hypoglycemia, though it rose strongly with arginine: the alpha cells could secrete but did not respond to falling glucose. Glucagon itself is an approved rescue medicine for severe hypoglycemia in people with diabetes. It is also approved as a diagnostic aid in radiology, where it briefly slows movement of the gastrointestinal tract.

The glucagon receptor in peptide research

Mazdutide and survodutide: GLP-1/glucagon dual agonists

Dual agonists pair GLP-1’s glucose-dependent insulin-releasing action with glucagon’s effects on energy expenditure and liver fat metabolism in one molecule. Mazdutide was tested in GLORY-1, a 48-week phase 3 trial in 610 Chinese adults with obesity or overweight: mean body-weight change at week 48 was about −11% and −14% in the two active arms against +0.3% with placebo, and the most common adverse events were gastrointestinal. Survodutide was tested in a 48-week phase 2 trial in 293 adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis: 47%, 62% and 43% of the three active arms met the primary endpoint of MASH improvement without worsening fibrosis, against 14% with placebo. Our mazdutide vs survodutide comparison sets the two side by side.

Retatrutide adds GIP-receptor agonism to make a GIP/GLP-1/glucagon triple agonist (see our TRIUMPH trials article). Because these trials compare whole molecules with placebo, they cannot show how much of any effect comes from the glucagon receptor.

Antagonists: lower glucose, at a cost

Glucagon-receptor antagonists did lower glucose in trials, but across the class they also caused fatty liver, raised blood pressure and increased liver aminotransferases or cholesterol, and development was halted. With one antagonist, LY2409021, human studies recorded more liver fat, higher total cholesterol and a rise in body weight. The liver–alpha-cell axis predicts a further liability: blocking glucagon’s action raises plasma amino acids, which drive alpha cells to multiply.

What’s established and what isn’t

Sourcing glucagon-pathway peptides in Canada

For in-vitro work on the glucagon receptor or its co-agonists, the documentation questions match those for any research peptide; our guide to research peptides in Canada covers the basics. These are the points worth putting to any Canadian peptide supplier:

• Identity and purity for your batch. Ask for a certificate with an HPLC purity result and a mass-spectrometry identity check for the batch you receive, with a batch number that matches the vial. Our peptide COA guide explains what else it should contain.
• The right molecule. Native glucagon, a GLP-1/glucagon dual agonist and an amylin analogue have different sequences and masses; the observed mass should match the compound on the label.
• Storage. Keep lyophilized material cold, dry and dark until it is needed; see the peptide storage guide.

MazdutideGLP-1/glucagon dual agonist, tested against placebo in the phase 3 GLORY-1 trialView product SurvodutideGlucagon/GLP-1 dual agonist, studied in a phase 2 MASH and fibrosis trialView product CagrilintideLong-acting amylin analogue; amylin signalling restrains post-meal glucagonView product

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