Three incretin receptors: what GLP-1, GIP and glucagon each do

Several weight-loss peptides copy signals the gut already sends after a meal. The three that matter most here are GLP-1, GIP and glucagon, each with its own receptor. Drugs built on these receptors differ mainly in which ones they hit and how strongly. This article covers what each receptor is known to do, what the trial data can and cannot say about each one, and where the evidence stops.

GLP-1 is the best-characterized of the three. Tirzepatide adds GIP activity to GLP-1, and retatrutide adds glucagon receptor activity on top of both. The trials show that adding receptors is associated with larger weight changes in the reported data. No published study we opened isolates how much of that effect each receptor produces, and that gap is the main limit on any receptor-by-receptor explanation.

What does GLP-1 do?

Holst's 2007 review in Physiological Reviews describes GLP-1 as a 30-amino-acid peptide produced in intestinal L-cells and released in response to meal intake. Its main actions are to stimulate insulin secretion and inhibit glucagon secretion, which limits the rise in blood glucose after eating. It also inhibits gastrointestinal motility and secretion, which is why it is described as an enterogastrone and part of the ileal brake. The review adds that GLP-1 appears to be a physiological regulator of appetite and food intake.

The hormone is broken down very quickly by the enzyme dipeptidyl peptidase IV, often before it leaves the gut. Holst argues that this raises the possibility that some GLP-1 actions are relayed by sensory neurons in the intestine and liver that express the GLP-1 receptor, rather than by the hormone circulating in the blood. The review presents this as a possibility, not an established mechanism, and that distinction matters for how much weight the circulating-hormone model can carry.

Why was GIP added?

GIP, glucose-dependent insulinotropic polypeptide, is the second incretin. The 2025 review by James-Okoro and colleagues in Frontiers in Endocrinology states that unimolecular co-agonists targeting both GIP and GLP-1 receptors offer more effective treatment strategies for obesity and type 2 diabetes than GLP-1 receptor agonists alone. The reference trial for that claim in people is SURMOUNT-1, published in NEJM in 2022.

SURMOUNT-1 randomized 2,539 adults with obesity, or overweight plus at least one weight-related complication, to once-weekly tirzepatide at 5, 10 or 15 mg or placebo for 72 weeks, including a 20-week dose-escalation period. Mean weight change was -15.0%, -19.5% and -20.9% across the three doses, against -3.1% on placebo. Discontinuation because of adverse events was 4.3%, 7.1% and 6.2% in the tirzepatide groups and 2.6% on placebo. The most common adverse events were gastrointestinal, mostly mild to moderate, and clustered during dose escalation.

Is GIP receptor activity the useful part, or is blocking it?

This is still disputed. The James-Okoro review notes that both agonism and antagonism of the GIP receptor (GIPR) produce weight loss and metabolic improvement in preclinical models, so animal data alone do not settle the direction of effect. What the review does establish is that GIPR signalling in the central nervous system, in regions that regulate energy balance, is essential for GIP's action on appetite. That places part of the mechanism in the brain.

The same review does not say which drug strategy works best in people. Tirzepatide is an agonist at both the GIP and GLP-1 receptors, and the GIP contribution to its weight effect has not been isolated in the human trials we opened. A receptor-level account of tirzepatide's results is therefore an inference from preclinical and review work, not a demonstrated mechanism.

What does the glucagon receptor add?

Jakubowska, Roux and Viljoen's 2024 update in Endocrinology and Metabolism places retatrutide in the GLP-1/GIP/glucagon triagonist category and summarizes its phase 2 result: 24.2% weight loss at 48 weeks with the 12 mg dose. The abstract does not establish what the glucagon receptor contributes to that figure. The phase 2 trial, first-authored by Jastreboff and published in NEJM in 2023, reports results for the whole molecule at each dose, not for each receptor separately.

The phase 2 trial randomized 338 adults to retatrutide or placebo for 48 weeks. At 24 weeks, weight change ranged from -7.2% to -17.5% across the retatrutide groups, against -1.6% on placebo. At 48 weeks the 12 mg arm reached -24.2%, against -2.1% on placebo. Gastrointestinal events were dose-related and were partly reduced when the trial used a 2 mg starting dose instead of 4 mg. Heart rate rose in a dose-dependent way, peaked at 24 weeks and declined afterward. Whether the glucagon component drives any of this is a hypothesis that the current published data cannot test on their own.

What the receptor map does not settle

Three limits apply. First, these trials are not head-to-head. SURMOUNT-1 enrolled about seven times as many people as the retatrutide phase 2 trial and ran 72 weeks rather than 48, so the figures in the table cannot be ranked on their face. Second, most of the receptor-level explanation comes from preclinical work and review articles, and the reviews we opened describe key parts of it as unresolved. Third, neither trial report we opened covers outcomes beyond its treatment period, so the weight curves say nothing about what happens after treatment stops.

Where research-grade material fits

Approved prescription products containing tirzepatide exist. Research-grade material is not the approved product, and it is not the product studied in SURMOUNT-1 or the phase 2 retatrutide trial. Retatrutide is investigational: the papers we opened describe trial work, not an approved product. Anyone seeking treatment for obesity should speak to a physician about approved options. Our research-grade versus prescription article covers the regulatory side in more detail.

Bottom line

The GLP-1 receptor has the strongest mechanistic support of the three, going back to physiology work such as Holst's 2007 review. The GIP receptor's contribution to appetite is real in the brain, but whether agonism or antagonism is the better strategy is still debated. The glucagon receptor's contribution to retatrutide's weight effect is not separated in the published record we opened. For compound detail, see our tirzepatide profile and retatrutide profile, and our semaglutide versus tirzepatide comparison for a head-to-head trial design. The price-per-vial comparison covers the compounds Core Power Peptides stocks.