How Mounjaro Works: GIP and GLP-1 Explained

Mounjaro (tirzepatide) works by copying the action of two natural gut hormones, GLP-1 and GIP, that your body releases after you eat. By activating the receptors for both hormones, it signals fullness to the brain, quietens hunger and thoughts about food, slows how fast the stomach empties and helps the pancreas release insulin when blood sugar rises. The overall result is that most people eat less without feeling as hungry, which leads to gradual weight loss. It does this for a whole week from a single injection because the molecule has been engineered to last far longer than the hormones it imitates.

This guide explains the science in plain English: what incretin hormones are, why acting on two receptors may matter, how the effects show up in day-to-day life, and what researchers still do not know. For a broader overview of treatment, see our complete guide to Mounjaro in the UK or the Mounjaro hub.

The basics: what are incretin hormones?

When you eat, cells lining your gut release several hormones into the bloodstream. Two of the most important are:

• GLP-1 (glucagon-like peptide-1), produced mainly by L-cells in the lower small intestine and colon
• GIP (glucose-dependent insulinotropic polypeptide), produced mainly by K-cells in the upper small intestine

These are called incretins. The name comes from the "incretin effect": scientists noticed decades ago that glucose taken by mouth triggers a much bigger insulin response than the same amount of glucose given directly into a vein. The difference is explained by these gut hormones, which tell the pancreas that food is on its way.

Beyond insulin, incretins form part of a wider communication network between the gut, the pancreas, fat tissue and the brain. That network helps decide when you feel hungry, when you feel satisfied and how your body stores and uses energy.

Why the natural hormones cannot be used as medicines

Natural GLP-1 and GIP are broken down within minutes by an enzyme called DPP-4 (dipeptidyl peptidase-4) and cleared by the kidneys. Giving them as medicines would require a continuous infusion. The breakthrough behind modern weight-loss medicines was designing molecules that resist that breakdown and stay in the body for days.

What makes tirzepatide different

Tirzepatide is a synthetic peptide, a short chain of amino acids. Its backbone is based on the natural GIP sequence, but it has been modified so that it also activates the GLP-1 receptor. It is therefore described as a dual GIP and GLP-1 receptor agonist (an agonist is something that switches a receptor on).

An "imbalanced" dual agonist

Laboratory research published by Eli Lilly scientists (Coskun and colleagues in Molecular Metabolism, 2018, and Willard and colleagues in JCI Insight, 2020) found that tirzepatide is not an equal partner at the two receptors. It binds the GIP receptor with an affinity similar to natural GIP, but binds the GLP-1 receptor less strongly than natural GLP-1. It has been described as "imbalanced", favouring GIP.

The same research found that at the GLP-1 receptor, tirzepatide signals in a slightly different way from natural GLP-1, a property called biased agonism. In simple terms, it seems to switch the receptor on while causing less of the process that pulls receptors back inside the cell. Researchers have suggested this may help sustain its effect, though how much this matters in people is not yet clear.

Why it lasts a week

Tirzepatide carries a fatty acid side chain (a C20 fatty diacid) attached through a linker. This lets it bind reversibly to albumin, the most abundant protein in blood. While bound, it is protected from breakdown and from being filtered out by the kidneys. The Mounjaro SmPC gives its half-life as about five days, and steady blood levels build up over around four weeks of weekly dosing.

How the effects show up in the body

1. Appetite and the brain

The most important effect for weight loss is on appetite. GLP-1 receptors are found in brain areas that regulate hunger and fullness, including the hypothalamus and the brainstem. GIP receptors are also found in some of these regions. Activating them sends signals that:

• increase feelings of fullness (satiety) during and after meals
• reduce hunger between meals
• may reduce the reward value of highly palatable foods

People taking Mounjaro often describe the last effect as quieter "food noise": fewer intrusive thoughts about food, less snacking and less interest in second helpings. This is a commonly reported experience rather than a formally defined clinical measure, and not everyone notices it to the same degree.

Studies of GLP-1-based medicines suggest that the weight loss comes mainly from eating fewer calories, rather than from burning more. Our article on how Wegovy works covers the GLP-1 brain pathways in more detail.

2. Slower stomach emptying

Tirzepatide slows the rate at which food leaves the stomach. This helps you feel full for longer after a meal and smooths out rises in blood sugar. Research on GLP-1 medicines suggests this effect is strongest when treatment starts or after a dose increase, and tends to lessen over time.

Slower stomach emptying also explains several practical issues:

• Digestive side effects such as nausea, fullness, burping and reflux, especially after large or fatty meals
• Effects on other medicines taken by mouth, including oral contraceptives, whose absorption may be reduced or delayed
• Anaesthesia precautions, because food may remain in the stomach longer than expected, increasing the risk of aspiration during sedation or general anaesthetic

3. Insulin and blood sugar

Both GIP and GLP-1 prompt the pancreas to release insulin, but only when blood sugar is raised. This "glucose-dependent" action is important: when blood sugar returns to normal, the extra insulin release stops. That is why tirzepatide on its own carries a low risk of hypoglycaemia (low blood sugar). The risk rises when it is combined with insulin or sulfonylureas, which push blood sugar down regardless of level.

GLP-1 activity also reduces glucagon, a hormone that raises blood sugar, when blood sugar is high. Together, these effects are why tirzepatide was first licensed for type 2 diabetes. In the SURPASS-2 trial in people with type 2 diabetes, published in the New England Journal of Medicine in 2021, tirzepatide lowered HbA1c (a measure of long-term blood sugar) and body weight more than semaglutide 1mg.

4. Fat tissue and insulin sensitivity

GIP receptors are found on fat cells. Animal and laboratory work suggests GIP may influence how fat tissue stores and handles fat, and may improve insulin sensitivity. Some of the improvement in insulin sensitivity seen in trials is likely to be a result of weight loss itself, and separating the two effects is difficult. This is an area of active research.

5. Nausea signalling

One intriguing finding from animal research is that GIP receptor activation may reduce nausea and vomiting signals in the brainstem. Some scientists have proposed that this could help explain why tirzepatide can be given at doses that activate the GLP-1 receptor substantially without proportionally more nausea. However, nausea is still one of the most common side effects of Mounjaro, so this remains a hypothesis rather than an established benefit. See our Mounjaro side effects guide for how side effects are managed.

The GIP puzzle

GIP is the less understood of the two hormones, and its role in weight is genuinely debated.

For years, some researchers thought blocking GIP might help weight loss, because mice lacking GIP receptors are resistant to weight gain on high-fat diets. Yet tirzepatide, which activates GIP receptors, produces more weight loss than GLP-1 agonists alone. To add to the puzzle, experimental medicines that block the GIP receptor while activating GLP-1 have also shown weight loss in early studies.

One explanation that has been proposed is that prolonged activation of the GIP receptor may eventually desensitise it, producing an effect similar to blocking it. Another is that GIP's benefits come mainly through the brain and nausea pathways rather than fat tissue. The honest answer is that the mechanism is not fully settled. What is established is the clinical result: in SURMOUNT-5, tirzepatide produced greater average weight loss than semaglutide at 72 weeks. Our guide to tirzepatide in the UK explores the science further.

From mechanism to results

The effects above add up to the results seen in clinical trials. In SURMOUNT-1, adults without diabetes lost on average about 15% to 21% of their body weight over 72 weeks, depending on dose, compared with about 3% on placebo. The pattern over time reflects the mechanism:

For the trial data in more detail, see Mounjaro results: what the trials show over time.

Why a plateau is expected

As you lose weight, your body needs fewer calories, and it also makes adaptive changes that push appetite back up. At some point, the reduced intake produced by tirzepatide matches your new, lower energy needs and weight stabilises. This plateau does not usually mean the medicine has stopped working. Evidence from SURMOUNT-4, in which people who switched to placebo regained a large share of their lost weight, suggests the effect continues as long as treatment does. Our guide to weight loss plateaus on GLP-1 medication looks at this in more depth.

Common misconceptions

"Mounjaro burns fat." It does not directly burn fat. It helps you eat less, and the body then uses stored energy, including fat. Some lean tissue is also lost, which is why protein and strength training are often recommended.

"It speeds up your metabolism." There is no good evidence of a meaningful increase in calorie burning. If anything, metabolic rate tends to fall as body size falls, as with any weight loss.

"It works the same for everyone." Responses vary widely. Genetics, diabetes status, the dose reached, other medicines and lifestyle all play a part. Some people lose much more than average, and some lose little.

"It is just a diabetes drug used off-label." In the UK, Mounjaro is licensed by the MHRA for weight management as well as for type 2 diabetes, within defined BMI criteria.

"You can stop once you have lost the weight." You can stop, but trials show that appetite typically returns and regain is common. Decisions about stopping or reducing the dose should be planned with your prescriber. See our Mounjaro maintenance guide.

How this fits with other weight-loss medicines

Understanding the mechanism helps explain the differences between options:

• Semaglutide (Wegovy) acts on the GLP-1 receptor only. It has strong evidence for weight loss and, from the SELECT trial, for reducing cardiovascular events in people with established heart disease. See Mounjaro vs Wegovy.
• Liraglutide (Saxenda) is an older GLP-1 agonist with a shorter half-life, so it is injected daily.
• Oral GLP-1 medicines include oral semaglutide and orforglipron (Foundayo), a non-peptide molecule that activates the GLP-1 receptor. At the time of writing, both have been authorised by the MHRA for weight management in 2026; check the current SmPC and NICE guidance for UK details. See our guide to oral GLP-1 medications.
• Orlistat works in a completely different way, reducing fat absorption in the gut rather than acting on appetite hormones.

For a general introduction to this family of medicines, read What are GLP-1 medications?. If you are looking at treatment routes, our providers page compares regulated services, and our prices page explains what affects cost.

Why people respond differently

Even though tirzepatide acts on the same receptors in everyone, the size of the response varies considerably. Researchers think several factors contribute:

• Diabetes status. People with type 2 diabetes tend to lose less weight on GLP-1-based medicines, as seen in SURMOUNT-2.
• Dose reached. Higher doses activate the receptors more strongly and produced more weight loss on average.
• Biology. Differences in genetics, gut hormones and brain appetite pathways may affect how strongly someone responds, though this is not yet well understood.
• Other medicines. Some medicines, such as certain antidepressants, antipsychotics and steroids, can increase appetite or weight.
• Eating patterns and environment. The medicine reduces appetite, but food choices, sleep, stress and activity still influence results.

This variation is one reason why NICE TA1026 includes a review point at six months, and why prescribers tailor doses to the individual. See What if GLP-1 treatment doesn't work for you?.

Why the mechanism matters for safety

Several safety considerations follow directly from how tirzepatide works:

• Gradual dose increases give the digestive system time to adapt to slower stomach emptying and stronger appetite signals.
• Hydration matters, because eating and drinking less, plus any vomiting or diarrhoea, can lead to dehydration and, in some cases, kidney problems.
• Contraception needs thought, because slower stomach emptying may affect how well the pill is absorbed. The SmPC advises considering a non-oral method or adding a barrier method for four weeks after starting and after each dose increase.
• Diabetes medicines may need adjusting, because combining tirzepatide with insulin or sulfonylureas increases the risk of low blood sugar.
• Procedures under anaesthetic require telling the medical team, because the stomach may not be empty even after fasting.

These are reasons why prescribing decisions belong with a qualified prescriber who knows your full medical history.

When to speak to a professional

Talk to your GP, pharmacist or prescriber if you are considering Mounjaro, so they can check whether it is suitable alongside your other health conditions and medicines. Contact them during treatment if:

• side effects are preventing you from eating or drinking enough
• you take diabetes medicines and notice symptoms of low blood sugar, such as shakiness, sweating or confusion
• you are planning a pregnancy, or think you may be pregnant
• you are due to have surgery or a procedure under sedation or anaesthetic

Seek urgent medical help (NHS 111, or 999 in an emergency) if you have:

• severe, persistent abdominal pain, which may spread to your back, with or without vomiting
• pain in the upper right abdomen with fever or yellowing of the skin or eyes
• signs of severe dehydration, such as passing very little urine, dizziness or confusion
• swelling of the face, lips or throat, or difficulty breathing