Glucagon Receptor Research: From Counter-Regulatory Hormone to Agonist Target

The glucagon receptor was avoided in metabolic research for decades. What changed, what the liver–alpha cell axis is, and what the trials report.

By Published Updated

For most of the century since glucagon was isolated, the pharmacological interest in its receptor ran in one direction only: block it. Glucagon raises blood glucose, diabetes is a disease of raised blood glucose, and the arithmetic seemed to settle the matter.

The multi-agonist programmes of the last decade run the opposite way. They deliberately add glucagon receptor agonism to molecules intended for metabolic use — and they do it by pairing it with incretin receptor activity that offsets the glycaemic consequence. This article sets out what the receptor is, why the reversal happened, and what the published evidence at each level actually reports. It describes research and contains no guidance of any kind on handling any material.

What the receptor is

The glucagon receptor, GCGR, is a class B1 — secretin-like — G protein-coupled receptor. It was cloned from rat by expression cloning in 1993, in the paper that also characterised its signalling properties [1]. Like the other class B1 receptors in this part of the library, it couples through Gs to adenylate cyclase, raising intracellular cyclic AMP.

Its ligand, glucagon, is a 29-residue peptide secreted by pancreatic alpha cells. Glucagon and GLP-1 are both products of the same precursor, proglucagon, processed differently in different cells — which is why the two hormones share substantial sequence homology, why their receptors have overlapping recognition requirements, and ultimately why a single engineered peptide can activate both [2].

The receptor's principal tissue is liver. Hepatic glucagon receptor signalling drives glycogenolysis and gluconeogenesis, which is the action that made it a counter-regulatory hormone in the textbook account. Signalling in adipose tissue and effects on whole-body metabolic rate are the parts of its biology that the agonist programmes are built on [18].

The centenary review of glucagon research, published in 2023, is a useful single reference for how the understanding of this receptor has changed across that history [11].

Why the field reversed direction

Three developments, in combination, changed what the receptor looked like as a target.

The liver–alpha cell axis. The relationship between hepatic glucagon signalling and alpha-cell glucagon secretion was re-described as a feedback loop rather than a one-way hormonal action, with implications for what happens when the receptor is blocked chronically [4]. A related line of work re-characterised alpha cells as amino acid sensors, reframing glucagon's primary physiological role around amino acid metabolism rather than around glucose alone [6].

Glucagon resistance. The idea that the receptor's signalling can be impaired in metabolic disease — that glucagon resistance exists as a phenomenon in its own right, analogous to insulin resistance — was reviewed as a distinct concept [5]. If the receptor is under-signalling rather than over-signalling in a given context, blocking it is not the obvious move.

The offsetting trick. The decisive practical development was the demonstration that glucagon receptor agonism's glycaemic liability could be neutralised inside a single molecule by incretin receptor activity, rather than requiring a second drug. That is the explicit premise of the tri-agonist design [9].

The broader case for glucagon signalling as a target across obesity, liver disease and cardio-kidney-metabolic conditions has since been set out as a review in its own right [18].

What the preclinical research established

Animal research

The reversal was argued in rodents before it was tested in people, and the rodent work is where the contribution of the glucagon arm was actually isolated.

A rationally designed monomeric peptide triagonist at the GIP, GLP-1 and glucagon receptors was reported in 2015 and characterised in rodent models of obesity and diabetes — the paper that established a single chain could carry all three activities and behave differently from its parts [3]. Successive generations of GLP-1/GIP/glucagon triple agonists were later compared in obese mice, examining how changing the balance between the three activities changes what the molecule does [8].

The most specific result for the glucagon arm came with retatrutide's discovery paper. In diet-induced obese mice, body-mass reduction separated into two contributions: reduced calorie intake attributable to the GIP and GLP-1 receptor arms, and an increase in whole-body metabolic rate attributable to the glucagon receptor arm, added on top [9]. That is the mechanistic claim the entire agonist programme rests on, and it is a rodent result.

It is worth noting the contrast with the incretin side directly. Rodent work on a single-receptor GLP-1 analogue reported body-mass reduction occurring without a decrease in whole-body metabolic rate [7] — that is, the incretin arm acts on intake, and the metabolic-rate contribution is what the glucagon arm is claimed to add.

Diet-induced obesity models in rodents are a standard preclinical tool and a poor predictor of human results in this field specifically. Findings described in this section were observed in animals, and nothing in them establishes anything about humans.

What the cell-based pharmacology shows

In vitro research

Two things are established at the receptor level and constrain how agonists here behave.

Sequence homology within the proglucagon family is what makes co-agonism possible. Glucagon and GLP-1 derive from the same precursor and share substantial sequence homology, and the receptors have overlapping recognition requirements. The engineering problem in a glucagon-containing multi-agonist is therefore not how to make one chain bind two receptors — that is achievable — but how to tune the ratio between them [1, 2].

The ratio is the design parameter. Retatrutide is characterised as balanced between the glucagon and GLP-1 receptors, with relatively greater activity at the GIP receptor [9]. In the glucagon–GLP-1 dual agonists, which carry no GIP arm, the same ratio question arises with one fewer variable.

The usual cautions apply and apply particularly here. In vitro potency at a cloned receptor in a transfected cell line is not a proportional predictor of effect in tissue, and the glucagon receptor's principal tissue — liver — receives a different exposure from a subcutaneously administered, albumin-bound peptide than a pancreatic islet does.

What the human research reports

Human clinical research

Results from pharmaceutical clinical trials describe the investigational material and populations used in those studies and should not be interpreted as establishing the effects of research-grade materials offered for laboratory use.

No compound engaging only the glucagon receptor is in clinical development for metabolic use. Every clinical result attributed to glucagon receptor agonism comes from a molecule that also engages at least the GLP-1 receptor — by design, since the offsetting of the glycaemic liability is the premise. So the clinical record below is the record of glucagon-containing molecules.

Glucagon plus GLP-1, without GIP

This is the branch that comes closest to isolating the glucagon question, because it differs from a single-receptor GLP-1 analogue in one arm rather than two.

Survodutide, a glucagon and GLP-1 receptor dual agonist, reported a randomised, double-blind, placebo-controlled phase 2 amount-finding trial in obesity [15]. A separate phase 2 trial in people with type 2 diabetes compared it against placebo and against open-label semaglutide, reporting effects on glycated haemoglobin and bodyweight [14] — a design that is unusual in this branch and useful precisely because it includes an active comparator, albeit open-label. A phase 3 trial in adults with obesity has since reported [20].

Mazdutide, another glucagon and GLP-1 receptor dual agonist, reported a phase 3 trial in Chinese adults with obesity or overweight [17].

Glucagon plus both incretin receptors

The triple agonist record is younger and belongs principally to one compound. A phase 1b trial in 72 adults with type 2 diabetes reported a plasma half-life near six days and placebo-adjusted glycated haemoglobin reductions of 1.2% to 1.6% in the three highest groups over 12 weeks [10]. A phase 2 trial in obesity randomised 338 adults and reported least-squares mean change in body weight at 48 weeks of −8.7% to −24.2% across groups against −2.1% for placebo [12]. A phase 2 trial in type 2 diabetes randomised 281 adults against placebo and dulaglutide 1.5 mg [13].

Most relevant to the glucagon arm specifically, a phase 2a substudy in 98 participants with metabolic dysfunction-associated steatotic liver disease reported mean relative change in liver fat at 24 weeks of −42.9% to −82.4% across groups against +0.3% for placebo [16]. Liver is the glucagon receptor's principal tissue, which makes hepatic endpoints the place where a glucagon contribution would be most expected — but the substudy cannot attribute its result to that arm, because the molecule engages three receptors and the endpoint was imaging rather than histology, with no measure of fibrosis.

The first phase 3 result, TRANSCEND-T2D-1, randomised 537 adults with type 2 diabetes and reported mean glycated haemoglobin change of −1.69% to −1.94% against −0.81% for placebo at 40 weeks — which addresses the central historical worry about glucagon agonism directly, since a glucagon-containing molecule lowering glycated haemoglobin in a phase 3 trial is the offsetting premise being tested at scale [19].

What the clinical record does not establish

No trial has isolated the glucagon receptor arm in humans. No pair of otherwise-identical molecules differing only in glucagon receptor activity has been compared. No outcome trial — counting deaths, myocardial infarctions, strokes or kidney failure — has reported for any glucagon-containing multi-agonist. And no compound engaging the glucagon receptor in a metabolic programme is approved for any indication, in the United States or elsewhere.

What remains unsettled

Whether the metabolic-rate contribution demonstrated in mice occurs in people. The decomposition of effect into incretin and glucagon contributions is a rodent result [9]. No human study has separated them.

What the right ratio is. The balance between glucagon and incretin receptor activity is tunable, successive molecules have been built with different balances [8], and no clinical comparison of different balances exists.

Whether chronic agonism interacts with the liver–alpha cell axis. The feedback relationship between hepatic glucagon signalling and alpha-cell secretion was characterised in the context of receptor blockade [4]. What chronic agonism does to that loop is not addressed by the published trial literature.

All the clinical research described here studied pharmaceutical investigational material, manufactured to a regulatory standard, administered under registered protocols in defined populations under clinical supervision. None of it is research into, or evidence about, research-grade material supplied for laboratory use.

Frequently Asked Questions

What is the glucagon receptor?
A class B1, secretin-like G protein-coupled receptor, cloned from rat by expression cloning in 1993 [1]. It couples through Gs to raise intracellular cyclic AMP. Its principal tissue is liver, where signalling drives glycogenolysis and gluconeogenesis; signalling in adipose tissue and effects on whole-body metabolic rate are the parts of its biology the agonist programmes are built on [18].
Why was glucagon receptor agonism avoided for so long?
Because unopposed glucagon action raises blood glucose, and the field's interest was in lowering it. The centenary review of glucagon research sets out how that framing developed and how it has changed [11]. The reversal depended on showing that the glycaemic liability could be offset inside one molecule by incretin receptor activity [9].
What is the liver–alpha cell axis?
The feedback relationship between hepatic glucagon receptor signalling and glucagon secretion by pancreatic alpha cells, re-described as a loop rather than a one-way action [4]. A related line of work re-characterised alpha cells as amino acid sensors, reframing glucagon's physiological role around amino acid metabolism rather than glucose alone [6].
Which compounds engage the glucagon receptor?
In the dual-agonist branch, survodutide and mazdutide combine glucagon and GLP-1 receptor activity without a GIP arm [15, 17]. In the triple-agonist branch, retatrutide adds the glucagon receptor to both incretin receptors [9]. None is approved for any indication.
Has any trial tested glucagon receptor agonism on its own?
No. Every clinical result attributed to glucagon receptor agonism comes from a molecule that also engages the GLP-1 receptor — by design, since offsetting the glycaemic consequence is the premise of the approach. No pair of otherwise-identical molecules differing only at the glucagon receptor has been compared in humans.
What did the animal research attribute to the glucagon arm?
An increase in whole-body metabolic rate. In diet-induced obese mice, body-mass reduction separated into reduced calorie intake attributable to the GIP and GLP-1 receptor arms and an increase in metabolic rate attributable to the glucagon arm [9]. Rodent work on a single-receptor GLP-1 analogue reported body-mass reduction without a decrease in metabolic rate [7], which is the contrast that makes the claim specific. Findings in animals establish nothing about humans.
Does glucagon come from the same gene as GLP-1?
From the same precursor. Glucagon and GLP-1 are both products of proglucagon, processed differently in different cells, which is why they share substantial sequence homology and why their receptors have overlapping recognition requirements [2]. That homology is what makes a single engineered peptide capable of activating both.

References

  1. Expression cloning and signaling properties of the rat glucagon receptor Science; 1993. PMID 8384375 doi:10.1126/science.8384375
  2. Biology of incretins: GLP-1 and GIP Gastroenterology; 2007. PMID 17498508 doi:10.1053/j.gastro.2007.03.054
  3. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents Nature Medicine; 2015. PMID 25485909 doi:10.1038/nm.3761
  4. The Liver-α-Cell Axis and Type 2 Diabetes Endocrine Reviews; 2019. PMID 30920583 doi:10.1210/er.2018-00251
  5. Glucagon Receptor Signaling and Glucagon Resistance International Journal of Molecular Sciences; 2019. PMID 31284506 doi:10.3390/ijms20133314
  6. A Primary Role for α-Cells as Amino Acid Sensors Diabetes; 2020. PMID 31653720 doi:10.2337/dbi19-0021
  7. Semaglutide lowers body weight in rodents via distributed neural pathways JCI Insight; 2020. PMID 32213703 doi:10.1172/jci.insight.133429
  8. Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice Molecular Metabolism; 2022. PMID 35809773 doi:10.1016/j.molmet.2022.101533
  9. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept Cell Metabolism; 2022. PMID 35985340 doi:10.1016/j.cmet.2022.07.013
  10. LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial The Lancet; 2022. PMID 36354040 doi:10.1016/S0140-6736(22)02033-5
  11. 100 years of glucagon and 100 more Diabetologia; 2023. PMID 37367959 doi:10.1007/s00125-023-05947-y
  12. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial The New England Journal of Medicine; 2023. PMID 37366315 doi:10.1056/NEJMoa2301972
  13. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA The Lancet; 2023. PMID 37385280 doi:10.1016/S0140-6736(23)01053-X
  14. Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial Diabetologia; 2024. PMID 38095657 doi:10.1007/s00125-023-06053-9
  15. Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial The Lancet Diabetes & Endocrinology; 2024. PMID 38330987 doi:10.1016/S2213-8587(23)00356-X
  16. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial Nature Medicine; 2024. PMID 38858523 doi:10.1038/s41591-024-03018-2
  17. Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight The New England Journal of Medicine; 2025. PMID 40421736 doi:10.1056/NEJMoa2411528
  18. Shared mechanistic pathways of glucagon signalling: Unlocking its potential for treating obesity, metabolic dysfunction-associated steatotic liver disease, and other cardio-kidney-metabolic conditions Diabetes, Obesity and Metabolism; 2025. PMID 41025406 doi:10.1111/dom.70148
  19. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial The Lancet; 2026. PMID 42250575 doi:10.1016/S0140-6736(26)00967-0
  20. Survodutide Once Weekly for the Treatment of Adults with Obesity The New England Journal of Medicine; 2026. PMID 42253238 doi:10.1056/NEJMoa2600751

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