One hormone, two names
The gene record kept by the US National Library of Medicine still lists GIP under its older name, gastric inhibitory polypeptide. The same record notes that it is a relatively poor inhibitor of stomach acid, which was the effect the old name described [5].
Its better-known job is captured by the newer name used in the drug labels and by the NIDDK: glucose-dependent insulinotropic polypeptide. Insulinotropic means it pushes the pancreas to release insulin, and glucose-dependent means that push depends on the level of sugar in the blood [1][6].
An incretin hormone
An incretin is a hormone from the gut that helps the body release insulin after a meal. The gene record describes GIP as an incretin that belongs to the glucagon family of hormones and calls it a potent stimulator of insulin secretion from the beta cells of the pancreas once food has been eaten and absorbed [5].
GIP works through a receptor on the surface of cells. When GIP binds, the receptor switches on a signalling enzyme called adenylyl cyclase inside the cell [5]. GLP-1, the better-known incretin, is the other gut hormone in this story. In the European Medicines Agency’s overview of Mounjaro®, both are gut-made hormones whose targets include the pancreas and the brain [4].
The incretin effect is why these hormones were noticed in the first place. A 2018 review describes it as an insulin response two to three times larger when glucose is swallowed than when the same glucose goes straight into a vein. GIP is made by K cells in the upper small intestine and GLP-1 by L cells lower in the gut [9].
MedlinePlus places tirzepatide in a class it calls incretin mimetics, medicines that copy the action of these gut hormones [7].
A hormone that lasts minutes
Intact GIP is written GIP(1-42), a chain of 42 amino acids. The enzyme dipeptidyl peptidase-4 (DPP-4) removes its first two, leaving GIP(3-42), a shorter form that no longer stimulates insulin [11].
In a study that used an assay detecting only the intact hormone, GIP infused into a vein had a plasma half-life of about 7 minutes in healthy volunteers and about 5 minutes in people with type 2 diabetes [11]. The study measured the hormone itself, not a medicine, but it shows the distance a GIP-based drug has to cover: the tirzepatide labels give a half-life of about 5 days and tie its length to a fatty acid chain that binds albumin [1].
What changes in type 2 diabetes
In people with type 2 diabetes the incretin effect is weakened or missing. The 2018 review puts this down mainly to a much smaller response of the diabetic pancreas to GIP, while GLP-1 keeps enough of its insulin-releasing and glucagon-lowering action to lower blood sugar when its receptor is stimulated with a drug. That, the authors write, is why GLP-1 became the parent compound of GLP-1 receptor agonists and DPP-4 inhibitors [9].
An older experiment shows the gap. In 1993, nine people with mild type 2 diabetes and nine matched volunteers received infusions of each hormone during a glucose clamp. The highest insulin response to GIP was 54% lower in the diabetes group, whereas with GLP-1 they reached 71% of the response of the volunteers, a difference that was not significant. GLP-1 also lowered glucagon; GIP did not [10]. With 18 participants and short infusions, this is a finding about mechanism rather than treatment.
That background explains the question behind the first Lilly paper on tirzepatide, then called LY3298176: whether the metabolic action of GIP adds anything to what selective GLP-1 receptor agonists already do [13].
| Point | GIP | GLP-1 |
|---|---|---|
| Where it is made | K cells in the upper small intestine [9] | L cells in the lower gut [9] |
| Insulin response in mild type 2 diabetes, 1993 study | Maximum effect 54% below that of volunteers without diabetes [10] | 71% of the volunteers’ response; difference not significant [10] |
| Effect on glucagon in the same study | No lowering [10] | Lowered in both groups [10] |
| Receptor listed on fat cells | Yes, in the EU product information [3] | Not listed for fat cells there [3] |
| Role in food intake, per the Zepbound® label | Nonclinical studies suggest it may add to the regulation of food intake [2] | Described as a physiological regulator of appetite and calorie intake [2] |
| Tirzepatide’s activity at this receptor | Similar to native GIP [3] | Lower than native GLP-1 [3] |
Where its receptors are found
Section 5.1 of the European product information for Mounjaro® lists where GIP and GLP-1 receptors are present: the alpha and beta cells of the pancreas, the heart, blood vessels, white blood cells, the gut and the kidney. GIP receptors are also found on fat cells, called adipocytes [3].
Both receptors are also present in brain areas that matter for appetite. The US labels for Mounjaro® and Zepbound® say the same about the brain, and add that animal studies showed tirzepatide reaching and activating nerve cells in regions that regulate food intake [2][3].
GIP inside a medicine
Section 11 of the Mounjaro® label says tirzepatide is based on the GIP sequence, with a few deliberate changes and a fatty acid chain attached. Section 12.1 classes it as an agonist at both the GIP receptor and the GLP-1 receptor, meaning it switches on the receptors the two natural hormones normally use [1]. The European text counts 39 amino acids in its chain, three fewer than intact GIP [3][11].
The European product information adds a comparison that the US label does not make. It says tirzepatide acts at the GIP receptor with a strength similar to natural GIP, while its activity at the GLP-1 receptor is lower than that of natural GLP-1 [3].
A 2020 laboratory study by a team made up mostly of Lilly scientists went a step further. Its calculations of receptor occupancy at clinically used doses put tirzepatide’s hold on the GIP receptor ahead of its hold on the GLP-1 receptor, and at the GIP receptor the drug behaved like the native hormone [12].
What the labels say GIP may add
The Zepbound® label is careful here. It calls GLP-1 a physiological regulator of appetite and calorie intake, but for GIP it goes no further than saying that nonclinical work points to a possible extra role in controlling food intake. Nonclinical means studies in animals or in the laboratory, not in people [2].
In the European text, animal studies suggest tirzepatide can change how fat is used through the GIP receptor, and in human fat cells grown in a dish it acted on GIP receptors to influence how the cells take up sugar and fat and break fat down. These are findings about cells and animals; the labels do not split the effects seen in clinical trials into a GIP part and a GLP-1 part [3].
Antibodies against natural GIP
Section 12.6 of the Mounjaro® label reports that in seven trials in adults with type 2 diabetes, 51% of people treated developed antibodies against tirzepatide. Antibodies that also recognised natural GIP were found in 34% of all treated patients, and antibodies recognising natural GLP-1 in 14% [1].
Antibodies that blocked natural GIP were rare: the label gives 0.9% of those with antibodies. The label saw no clinically meaningful change in drug levels or benefit linked to antibodies, though allergic-type and injection site reactions were more frequent in people who had them [1].
The Zepbound® label reports its own figures from the weight trials: 64.5% formed antibodies, 40% of treated patients had antibodies that also recognised native GIP and 16.5% native GLP-1, and 0.8% had antibodies that neutralised native GIP [2]. Across the phase 3 programme, the European text gives 45.1% to 65.1% for antibodies that appeared during treatment, and up to 1.2% for antibodies neutralising native GIP [3]. Both US labels warn that differences in testing methods make these rates hard to compare between studies [1][2].
Which medicines act on GIP
Among the medicines in the NIDDK table of approved weight treatments, tirzepatide (Zepbound®) is the one described as copying two hormones, GIP and GLP-1. Under the name Mounjaro®, the same ingredient is approved for type 2 diabetes. The labels for semaglutide, liraglutide and orforglipron (Foundayo™) describe them as GLP-1 receptor agonists, with no GIP action listed [6][14].
The NIDDK also notes that researchers are studying future medicines that regulate several gut hormones at once. Investigational compounds are not approved, and the FDA has warned companies that sell such products, for example retatrutide, to consumers [6][8].
Making sense of it in your own log
Knowing that tirzepatide acts on two receptors does not change how a dose is taken, but it helps when you read your label or talk to your clinician about appetite, meals and stomach symptoms.
Mounjaro® and Zepbound® are registered trademarks of Eli Lilly and Company, and Foundayo™ is a trademark of Eli Lilly and Company. PepLabo is not affiliated with or endorsed by Eli Lilly and Company.
