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Tirzepatide Mechanism of Action: Mounjaro for Diabetes & Weight Loss

Tirzepatide Mechanism of Action

Tirzepatide mechanism of action (MOA) is slightly different from Semaglutide, Dulaglutide, Liraglutide, and other GLP-1 analogs.

Tirzepatide has been approved by the FDA for the management of patients who have T2DM (diabetes mellitus) in conjunction with exercise and a diabetic diet.

It is considered to be more effective than Semaglutide (Ozempic and Wegovy) in reducing body weight.

How Does Tirzepatide Work?

Tirzepatide is similar to Ozempic in most of its actions as a weight loss and diabetes drug. However, it has some additional effects that could be resulting in extra weight loss and better antidiabetic effects.

Both Tirzepatide and Semaglutide (Ozempic, Wegovy, and Rybelsus) act as incretin mimetic drugs. They both enhance the effects of endogenous incretins.

What are incretins?

Incretins are hormones or peptides that are secreted by the gut in response to ingested food. The incretin effect was first observed when scientists did an experiment by measuring plasma insulin levels in response to oral vs intravenous glucose.

It was found that more insulin was released and hence the glucose peak was much smaller when glucose was ingested orally than when it was given via an intravenous infusion.

This glucose-lowering effect was termed the “incretin effect”, an acronym for INtestinal seCRETion of INsulin” in response to oral glucose.

The two most important Inrectins in our body that accounts for more than 90% of all the incretins are:

  1. GLP-1 (Glucagon-like peptide-1)
  2. GIP (Glucose-dependent insulinotropic peptide), previously termed as Gastric Inhibitory Peptide.

Tirzepatide Mechanism of Action: Mounjaro MOA

To understand the mechanism of action of Tirzepatide, we need to know how the GLP-1 and GIP work.

Semaglutide acts only on GLP-1 and hence, it is called a GLP-1 mimetic. On the other hand, Tirzepatide acts on both GLP-1 and GIP.

Thus Tirzepatide has a dual action. It activates the GLP-1 as well as the GIP.

We discuss the effects of these two incretins, GLP-1 and GIP, one by one.

GLP-1 (Glucagon-like peptide 1):

It is now well known that the incretin effect is markedly blunted in diabetic patients vs non-diabetic patients.

With the novel GLP-1 analogs such as Semaglutide (Ozempic, Wegovy, and Rybelsus), Trulicity (dulaglutide), and Victoza (Liraglutide), the treatment of diabetes has been revolutionized.

All the previously approved incretin mimetics target the GLP-1 receptors.

  • What is GLP-1?

GLP-1 is produced by the L cells of the intestines during the processing of proglucagon [Ref]. The L-cells are predominantly found in the Ileum. It is a Glucagon-like peptide that stimulates insulin and suppresses glucagon levels.

  • Target cells:

GLP-1 acts primarily on the pancreas. It enhances the secretion of insulin and suppression of glucagon in a glucose-dependent mechanism.

This results in a lowering of the post-prandial insulin spikes.

It also acts on the stomach and inhibits its motility. This results in delayed gastric emptying, early satiety or fullness, and loss of appetite. 

“A lawsuit has been filed on 2nd Aug 2023 alleging that these medications paralyze your stomach and cause stomach injuries”

In addition to its effects on the pancreas and stomach, GLP-1 receptors have also been found in the brain, lungs, kidneys, heart, and more recently in the adipose tissues as well.

GLP-1 receptors have not been found in the skeletal muscles and the liver [Ref].

In the human brain, the highest GLP-1 receptors have been found in the hypothalamus, cerebral cortex, thalamus, hippocampus, caudate-putamen, and globus pallidus.

  • Mechanism of action of GLP-1 as an Insulinotropic peptide:

GLP-1 secretes insulin in a glucose-dependent mechanism. Its insulinotropic effect is considered to be 100 times more potent than glucagon.

GLP-1 activation results in acute and chronic insulinotropic effects. Acute insulinotropic effects are executed by the stimulation of Beta-cells in the pancreas to release more insulin.

The chronic effects are carried out by the effects of GLP-1 stimulation resulting in the preservation of the Beta cells. GLP-1 activation inhibits Beta-cell apoptosis and stimulates Beta-cells proliferation.

This effect is more important to prevent Beta-cells exhaustion. Beta-cell exhaustion ultimately leads to an increase in medication requirement with time and more people land up requiring some form of Insulin.

  • The effect of GLP-1 on Glucagon:

GLP-1 receptor activation inhibits the release of glucagon from the alpha cells of the pancreas. Since Glucagon increases the plasma levels of glucose, its suppression will result in a lowering of blood glucose levels.

GLP-1 receptor activation directly as well as indirectly inhibits glucagon secretion. It causes the release of somatostatin from the δ-cells that directly inhibits the release of glucagon from alpha cells.

It also stimulates the β-cells to release insulin, zinc, amylin, and GABA all of which suppresses the release of glucagon.

Most of the glucagon release is suppressed by the endocrine and paracrine mechanisms rather than direct inhibition [Ref].

  • GLP-1 Effects on Bodyweight:

The effect of GLP-1 receptor activation on body weight is mediated by multiple mechanisms. Some of these effects are direct while most are indirect effects and mediated via the central nervous system.

The direct effects are related to gastric fullness as a result of slow movements of the stomach or delayed gastric emptying.

It has also been observed that GLP-1 receptor activation may in part cause weight loss by inhibiting the absorption of nutrients via the gastrointestinal tract.

However, most of the weight loss effects are mediated by the GUT-BRAIN axis. This communication between the enteric nervous system and the hypothalamus induces early satiety or fullness after eating.

It also inhibits or modulates the cravings for high-calorie food items. Hence patients on GLP-1 receptor activators such as Semaglutide, Liraglutide, and Tirzepatide lose their craving for carbohydrates and high-calorie food items. This is particularly helpful in patients with binge-eating disorders.


GIP (Glucose-dependent insulinotropic peptide):

Like the GLP-1, GIP is also released by the entero-endocrine cells of the stomach in response to food. It is released by the K cells of the gut. The K cells are the most abundant enteroendocrine cells and are present mostly in the duodenum.

Like the GLP-1 receptor activation, GIP activation also has potent glucose-dependent insulinotropic effects.

Apart from its insulinotropic effects, it also promotes the growth and survival of the B-cells of the pancreas and stimulates adipogenesis [Ref]

  • Target cells for GIP:

Most of the functions of GIP are similar to GLP-1. It acts on the Beta cells, like the GLP-1 receptors, and stimulates glucose-dependent insulin secretion.

GIP also acts on the parietal cells of the stomach and inhibits the secretion of gastrin. Thus, it inhibits the gastrin-dependent secretion of acid from the parietal cells of the stomach.

The receptors for GIP are also present in the fat cells, adrenal cortex, bones, heart, pituitary gland, and brain.

In the brain, these receptors are predominantly found in the hippocampus, the olfactory bulb, and the cerebral cortex.

  • Functions of GIP:

GIP lowers blood glucose via the entero-insular axis. This effect is similar to GLP-1 receptor activation. Entero-insular activation is the effect of insulin on the enteral hormones.

The entero-insular pathway of insulin production is activated when food enters the stomach. Hence, this is also called glucose-dependent insulin production.

Insulin then causes glycogen synthesis and inhibits lipolysis or fat breakdown.

GIP, apart from its effects on the pancreas, has extrapancreatic effects as well. It inhibits the secretion of stomach acid by inhibiting the release of gastrin from the parietal cells.

It also stimulates osteoblasts and inhibits osteoclasts. This effect on the bones is opposite to the GLP-1.

In addition, because the GIP receptors are widely found in the brain, it exerts a substantial effect on brain signaling, predominantly on the brain-gut axis.

Another important effect of GIP receptors is cortisol production in response to food intake. This is termed ACTH-independent macronodular adrenal hyperplasia (AIMAH).

Food causes the activation of GIP that stimulates the release of cortisol from the adrenal gland, resulting in food-induced Cushing’s syndrome [Ref].


Tirzepatide Mechanism of Action – A DUAL GLP-1/ GIP Receptor Activator:

The mechanism of action of Tirzepatide (Mounjaro) is via activation of both incretin hormones, GLP-1 and GIP. Activation of both these receptors causes glucose-dependent insulin release.

The dual activation of GLP-1 and GIP has additive effects. Hence, theoretically, and recently proven in clinical trials as well, Tirzepatide is a more potent antidiabetic drug compared to drugs that act only on the GLP-1 receptors.

Both GLP-1 and GIP have anti-apoptotic and Beta-cells proliferative effects. This Beta-cells preserving effect has been seen to be greater with GLP-1 receptor activation compared to GIP.

Another important effect of GLP-1 and GIP, apart from their effects on insulin release, is their opposing effects on glucagon production.

GLP-1 receptor activation, in hyperglycemic states (above 100 mg/dl), inhibits the release of glucagon. Since glucagon increases plasma glucose levels, its inhibition will result in a greater glucose-lowering effect.

GIP activation, on the other hand, stimulates the release of glucagon. Theoretically, this effect was thought to hinder the role of GIP receptor activators as an antidiabetic drug.

However, in clinical studies, the glucagon secretory effect of GIP activation was not seen during hyperglycemic states. The glucagon secretory effect was seen only in states of hypoglycemia [Ref].

GIP receptor activation has been linked to obesity in animal models. It has been linked with overnutrition and obesity. In animal models, the levels of adiponectin were much higher in GIPR-mutated animals vs those with intact GIPR.

GIPR mutations, in animals, resulted in high energy expenditure. In addition, these GIPR mutated animals also resulted in enhanced insulin secretion and reduced insulin resistance even in animals who had a defective leptin gene that usually results in hyperphagia and obesity [Ref].

The association of GIP with overnutrition and obesity seems contradictory to the latest Trizepatide weight loss results in humans.

However, like most other hormones, the effect of GIP on fat cells and its association with overnutrition and obesity can be explained in part by the “pulsatile release of hormones” hypothesis.

Thus, continuous activation of GIP by long-acting GIP agonists, like Tirzepatide, may block the adipose receptors and inactivate them (similar to GnRH, TRH, Growth hormones, and others).


In conclusion: Tirzepatide Mechanism of Action

Tirzepatide is a dual GIP/ GLP-1 agonist that causes insulin release in a glucose-dependent mechanism. It also suppresses satiety and hunger via the gut-brain cross-talk, the entero-neural axis.

The effect of GLP-1 and GIP on glucagon release is the opposite. However, GLP-1 does not have any effect on glucagon release in states of low blood glucose while GIP does not affect glucagon secretion in states of hyperglycemia.

Likewise, the effect of fat accumulation in adipocytes and their effect on bone remodeling is also the opposite. GLP-1 causes osteopenia while GIP activates osteoblasts and results in bone formation.


What do you think?

Written by Dr. Ahmed

I am Dr. Ahmed (MBBS; FCPS Medicine), an Internist and a practicing physician. I am in the medical field for over fifteen years working in one of the busiest hospitals and writing medical posts for over 5 years.

I love my family, my profession, my blog, nature, hiking, and simple life. Read more about me, my family, and my qualifications

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