By Dr. Asnat Raziel, bariatric surgeon specializing in obesity treatment, metabolic health and healthy longevity; Director of the Multidisciplinary Center for Obesity Treatment, Assia Medical, Assuta Ramat HaChayal, Tel Aviv
What is the GIP hormone, and why is everyone talking about it?
The GIP hormone is one of the two main gut hormones that regulate blood sugar after a meal. For many years, it stood in the shadow of its famous sibling, GLP-1. Over the past decade, however, the picture has flipped. Drugs that also act on GIP now lead the treatment of diabetes and obesity. That is why it is worth getting to know it up close.
Type 2 diabetes is one of the biggest health epidemics in the world today. Hundreds of millions of people live with it. In addition, it is linked to heart disease, kidney damage, nerve damage and early death. Modern research is looking for the root of the problem in order to develop precise treatments. The incretin system is one of the most promising directions in the field.
What are incretins and how do they work?
Incretins are hormones that gut cells release when food reaches the digestive tract. The two main ones are GLP-1 and GIP. Their job is to improve the body’s response to a meal. They work in several ways:
- They boost insulin release from beta cells in the pancreas, but only when blood sugar rises.
- They affect glucagon, a hormone that raises blood sugar.
- They act on the nervous system and on appetite.
Thanks to them, sugar we eat triggers a much stronger insulin response than the same amount of sugar given by IV. This is known as the incretin effect. According to a comprehensive review by incretin researchers, GIP actually plays the larger physiological role of the two. Both hormones work together, and their effects on insulin add up. In addition, researchers have found local production of these hormones in alpha cells of the pancreas. The meaning of this finding is still unclear.
The GIP hormone: from a surprising discovery to a new name
Researchers discovered the hormone in 1971. At first, they thought it inhibited acid secretion in the stomach. So they called it gastric inhibitory peptide. Later, it turned out that its main role is something else entirely: it stimulates insulin release in response to glucose. As a result, the hormone got a new name, glucose-dependent insulinotropic polypeptide. The initials, GIP, stayed the same.
The hormone comes from K cells in the upper part of the small intestine. These cells release it into the blood after eating.
How the GIP hormone stimulates insulin release
The process starts on your plate and moves forward in three steps:
- Food reaches the gut, and K cells release GIP.
- The hormone binds to its receptors in the pancreas.
- Beta cells release insulin, in line with the blood sugar level.
This is how the body keeps tight control of blood sugar after a meal. In type 2 diabetes, however, this mechanism breaks down. The hormones keep reaching the blood almost as usual, but the pancreas responds to them only weakly. According to a review in the journal Diabetologia, it is GIP that loses much of its ability to boost insulin in diabetes. GLP-1, by contrast, keeps most of its effect.
Glucagon: the difference between GIP and GLP-1
An important difference between the two hormones concerns glucagon. GLP-1 reduces its release. GIP, on the other hand, may actually increase it, depending on the blood sugar level. Glucagon makes the liver release sugar into the blood. It therefore protects against hypoglycemia, a dangerous drop in blood sugar. In other words, the combination of the two hormones allows fine-tuned control of blood sugar.
The GIP hormone, appetite and fat tissue
GLP-1 reduces appetite and slows stomach emptying. These effects are the basis of modern weight loss drugs. So what about GIP? Here the picture is less simple. In animal studies, the hormone also affected appetite and weight. According to the review, however, studies in humans have not yet confirmed this effect.
On the other hand, the hormone has clear effects on other tissues. For example, it promotes fat storage in fat tissue. It also takes part in bone renewal. Researchers are also studying its effect on insulin sensitivity and fat metabolism. You can read more about the signals that regulate hunger and fullness in my article on the physiology of satiety.
Tirzepatide: when the GIP hormone joined treatment
This new understanding led to drugs that act on several receptors at once. The first to reach the market was tirzepatide, known as Mounjaro. It activates both the GIP receptor and the GLP-1 receptor. According to a review in Nature Metabolism, the FDA approved it in 2022 for type 2 diabetes. Later, it was also approved for treating obesity.
Why does adding GIP improve results? The full answer is not yet known. According to the review in Diabetologia, researchers are studying how prolonged activation of the GIP receptor contributes to blood sugar control and weight loss. In the past, most researchers saw GIP as a hormone with no therapeutic value. Today, thanks to tirzepatide, they are rethinking that view. For more on the change this drug has brought to people with diabetes, see my article on Mounjaro for type 2 diabetes.
The SURMOUNT-1 trial included 2,539 adults with obesity and without diabetes. After 72 weeks, the highest dose (15 mg) led to an average weight loss of 20.9%. In the placebo group, weight loss was only 3.1%. Beyond that, in the SURMOUNT-5 trial, researchers compared tirzepatide directly with semaglutide, the active ingredient in Wegovy. After 72 weeks, patients on tirzepatide lost 20.2% of their weight, compared with 13.7% on semaglutide. You will find all the details about the drug in my complete guide to Mounjaro.
The GIP hormone paradox: activate it or block it?
Here comes one of the most surprising stories in metabolic medicine. Blocking the GIP receptor, combined with activating GLP-1, also leads to weight loss. For example, the investigational drug maridebart cafraglutide, known as MariTide, blocks the GIP receptor and activates the GLP-1 receptor. In a phase 2 trial, participants received it as a once-monthly injection. After 52 weeks, participants with obesity lost 12.3%–16.2% of their weight, compared with 2.5% on placebo.
Researchers are still trying to understand how two opposite approaches produce a similar result. Meanwhile, the next generation is already on its way. Retatrutide activates three receptors: GIP, GLP-1 and glucagon. You can read about it in my article on the investigational drug retatrutide. I also give a broad overview in my article on next-generation obesity drugs.
The bottom line on the GIP hormone
The GIP hormone is a small hormone with big potential. The gut releases it after a meal, and it stimulates insulin release from the pancreas. Together with GLP-1, it is part of a system that regulates blood sugar, appetite and metabolism. Understanding this system has already changed the treatment of diabetes and obesity. In the future, we will probably see new combinations that improve metabolic balance and also protect the heart. Ultimately, the right treatment is chosen together with your doctor, based on each person’s medical condition and goals.
The information in this article is general and does not replace personal medical advice.
References
Incretin hormones and type 2 diabetes
Gut hormone co-agonists for the treatment of obesity: from bench to bedside
Tirzepatide Once Weekly for the Treatment of Obesity
Tirzepatide as Compared with Semaglutide for the Treatment of Obesity
Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity – A Phase 2 Trial
The SURMOUNT trials were funded by Eli Lilly, the maker of tirzepatide. The MariTide trial was funded by Amgen.
