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Oxyntomodulin

Also known as OXM, glucagon-37, bioactive enteroglucagon

Gut hormone acting on both GLP-1 and glucagon receptors, the model for today's dual agonists.

early-clinical Metabolic & weight endogenous peptide

At a glance

Category
Metabolic & weight
Status
endogenous peptide
Route
subcutaneous or intravenous infusion in studies
Half-life
roughly 12 minutes in humans — it is cleaved rapidly by DPP-4 and cleared renally
Onset
appetite effects within the same meal; weight effects over weeks with repeated dosing
Molecular weight
approximately 4449 g/mol
Sequence
HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA (37 residues: the full 29-residue glucagon sequence followed by an eight-residue C-terminal extension, spacer peptide-1)

A naturally occurring human hormone released by intestinal L cells after eating. Native oxyntomodulin has never been developed into an approved medicine — its half-life is far too short — but it is the pharmacological blueprint for the dual GLP-1/glucagon receptor agonists now in late-stage development, such as survodutide and the glucagon arm of retatrutide. Synthetic oxyntomodulin is sold in small quantities as a research chemical.

Doping status: Prohibited (WADA S0 when used as a non-approved substance)

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Mechanism of action

Oxyntomodulin is a product of the proglucagon gene, processed in intestinal L cells by prohormone convertase 1/3 in parallel with GLP-1 and GLP-2. Structurally it is glucagon plus an eight-amino-acid C-terminal tail, and functionally it behaves as a weak dual agonist: it activates both the GLP-1 receptor and the glucagon receptor, but with roughly one to two orders of magnitude lower potency at each than the native ligand. There is no dedicated 'oxyntomodulin receptor'; its distinct profile comes from hitting two receptors at once.

The two arms do different things and the combination is the point. GLP-1 receptor activation suppresses appetite, slows gastric emptying and enhances glucose-dependent insulin secretion. Glucagon receptor activation raises energy expenditure and promotes hepatic lipolysis and fat oxidation. Acting alone, glucagon raises blood glucose — a problem. Acting together with GLP-1 agonism, the insulinotropic arm offsets the hyperglycaemic effect, leaving the increase in energy expenditure.

This is why oxyntomodulin produces weight loss through two routes rather than one: reduced intake plus increased expenditure. Human studies have measured both sides, and the expenditure side is the weaker of the two: in the 2015 infusion study oxygen uptake did not change significantly from baseline with oxyntomodulin, glucagon, GLP-1 or the glucagon-plus-GLP-1 combination, even though food intake and appetite fell 3. The strategy of pairing GLP-1 agonism with controlled glucagon agonism, and tuning the ratio, is the direct descendant of the two-arm rationale, but the expenditure half of it rests more on animal work than on measured human energy expenditure.

The peptide also has a modest gastric effect — its name comes from inhibition of gastric acid secretion from oxyntic (parietal) cells — but this is a minor feature relative to its metabolic actions. Its fatal pharmacological flaw is duration: DPP-4 cleaves it within minutes, so native oxyntomodulin requires continuous or thrice-daily dosing, which is why every serious drug programme has used engineered analogues rather than the natural sequence.

What the research shows

Oxyntomodulin has been studied in humans, but only in small, short, mechanistic trials — typically a few dozen participants over days to a few weeks. Those trials consistently show reduced food intake and modest weight loss, and they were influential enough to launch an entire drug class. But native oxyntomodulin itself has never been through a phase 3 trial and never will be, because its half-life makes it impractical. The strong clinical evidence belongs to its engineered successors, not to the native peptide.

Research in humans

The key studies came from the Imperial College group in London. A 2003 study in the Journal of Clinical Endocrinology and Metabolism showed that intravenous oxyntomodulin infusion suppressed appetite and reduced food intake at a buffet meal in healthy volunteers 1. A 2005 study in Diabetes gave subcutaneous oxyntomodulin three times daily for four weeks to overweight and obese subjects and reported a mean weight loss of roughly 2.3 kg versus about 0.5 kg on placebo, with reduced energy intake 2. Later work, including a 2015 study in the same journal, directly compared oxyntomodulin, glucagon, GLP-1 and combined glucagon-plus-GLP-1 infusions on food intake, appetite and resting energy expenditure 3, helping to resolve which effects belong to which receptor.

Animal and lab research

Rodent studies established that oxyntomodulin reduces food intake and body weight beyond what pair-feeding explains, implicating increased energy expenditure. Studies in GLP-1 receptor knockout mice showed the anorectic effect is largely GLP-1-receptor-dependent, while the energy expenditure component requires glucagon receptor signalling. This animal work is what defined the dual-agonist rationale.

Caveats. All human trials are small — tens of participants — and short, the longest being about four weeks. Dosing was three times daily by injection, which is not a viable long-term regimen and limits what can be concluded about sustained effect. Weight loss of around 2 kg over four weeks is modest and would not be competitive with modern incretin drugs. Long-term safety of chronic glucagon receptor agonism, particularly effects on hepatic glucose output, lipids and heart rate, is not established from these studies. No cardiovascular outcome data exist. Material sold as oxyntomodulin outside research settings is of unverified identity and purity.

What it is used for

  • Research tool for studying appetite regulation and dual incretin-glucagon pharmacology
  • The mechanistic template for approved and investigational dual GLP-1/glucagon agonists such as survodutide, and for the triple agonist retatrutide
  • Used occasionally on the grey market for weight loss, where its very short half-life makes it a poor practical choice compared with engineered long-acting analogues

Dosing

Dose
In published human trials: intravenous infusion at approximately 3.0 pmol/kg/min, or subcutaneous injection of approximately 400 nmol (roughly 1.8 mg) per dose
Frequency
Three times daily, 30 minutes before each main meal, self-administered for four weeks in the only repeated-dosing study published
Route
Subcutaneous or intravenous infusion
Duration
Up to four weeks in the longest published trial
  • These are study doses from small mechanistic trials, not an approved regimen. The longest published regimen is four weeks of thrice-daily subcutaneous injection 30 minutes before each meal, which produced a mean weight loss of 2.3 kg against 0.5 kg on placebo and a reduction in energy intake of 170-250 kcal per meal 2. No dosing schedule has been validated for chronic use.
  • The 12-minute half-life is the practical obstacle: dosing less often than three times daily has no published basis, and even that regimen only barely covers meals.
  • Doses circulating in online user protocols are not clinically validated and often ignore the pharmacokinetics entirely.
  • The engineered analogues in clinical development are dosed weekly and are not interchangeable with the native peptide at any dose.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Reconstitution

Vial sizes
5 mg, 10 mg
Solvent
Bacteriostatic water (0.9% benzyl alcohol) is used in practice; clinical studies used pharmacy-prepared sterile solutions
Storage
No published stability study for reconstituted oxyntomodulin. Peptides of this class are generally kept at 2-8 °C after reconstitution and in the freezer as powder, protected from light, but this has not been validated for this peptide.

Worked example

A 5 mg vial reconstituted with 2 ml of bacteriostatic water gives 2.5 mg/ml; the roughly 1.8 mg study dose would then be about 0.72 ml, or 72 units on a U100 insulin syringe.

There is no licensed injectable presentation; the 5 mg and 10 mg vial sizes are research material. Run the diluent down the side of the vial rather than directly onto the powder, and do not shake. The absence of any published stability data for reconstituted oxyntomodulin means in-use shelf life is a matter of general peptide practice rather than evidence.

Work it out for Oxyntomodulin

Safety

Side effects

  • Nausea — the most common effect, dose-dependent, as with all GLP-1 receptor agonism
  • Vomiting at higher doses
  • Reduced appetite and early satiety, which is the intended effect
  • Injection site reactions with three-times-daily subcutaneous dosing
  • Modest increases in heart rate, attributable to both receptor arms
  • Transient rises in blood glucose are possible from the glucagon arm, particularly if the GLP-1 arm is insufficient to offset it
  • Long-term and rare effects are unknown; no study has exceeded four weeks

Do not use if

  • Pregnancy, breastfeeding and wish to conceive
  • Gastroparesis or severe gastrointestinal disease — GLP-1 receptor agonism slows gastric emptying
  • Poorly controlled diabetes, where the glucagon receptor arm could worsen glycaemia
  • History of pancreatitis, by extrapolation from the GLP-1 class
  • Phaeochromocytoma or insulinoma, where glucagon receptor agonism is hazardous
  • Use outside a research setting: no body verifies the identity, potency or sterility of grey-market material

Interactions

Not systematically studied. On mechanistic grounds, the GLP-1 arm slows gastric emptying and can delay absorption of oral medication, and combination with insulin or sulfonylureas raises hypoglycaemia risk in the same way as licensed GLP-1 agonists. Conversely, the glucagon arm opposes glucose-lowering therapy and could destabilise glycaemic control. Combining native oxyntomodulin with a licensed GLP-1 or dual agonist stacks the same receptor pharmacology and has never been studied.

Sources