Tirzepatide’s Dual GIP/GLP-1 Receptor Agonism Drives Superior Insulin Secretion and Weight Loss, Confirmed in Human Islets Study Published in Nature Metabolism

Tirzepatide is developed by Eli Lilly and Company.DiabetesTherapeutic Drug. This is a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. Activation of the GLP-1 receptor reduces hunger, thereby decreasing food and calorie intake, while activation of the GIP receptor reduces food and calorie intake and increases energy expenditure. Tirzepatide is being rapidly approved as a novel weight-loss therapy and is expected to be launched by the end of the year.

Previous Phase 3 clinical trials showed that after 72 weeks of tirzepatide treatment, participants in the 15mg dose group experienced an average weight loss of up to 22.5% (24 kilograms). This is the first investigational drug in Phase 3 clinical trials to demonstrate an average weight reduction exceeding 20%, making it the most effective weight-loss drug to date.

On June 5, 2023, researchers from Duke University, the German Diabetes Research Center, and Eli Lilly published a paper titled **The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets** in the *Nature* sub-journal *Nature Metabolism*.

This study is the first to use human donor cells to demonstrate that tirzepatide is indeed a dual agonist of the GIP receptor and GLP-1 receptor, rather than merely a so-called super GLP-1 receptor agonist. The study also shows that tirzepatide's activation of the GIP receptor is essential for its stimulation of insulin secretion.

Jonathan Campbell, the corresponding author of the paper and a professor at Duke University School of Medicine, stated that understanding the multiple targeting mechanisms of tirzepatide opens up a whole new world for the development of better weight-loss and diabetes drugs.

Targeting glucagon-like peptide-1 (GLP-1) receptors for the treatment of diabetes has a long history. For patients with type 2 diabetes, GLP-1-based drugs can restore insulin production, thereby lowering blood sugar levels.HypoglycemiaMoreover, this drug can also increase the feeling of fullness and reduce appetite, thereby aiding in weight loss. This makes GLP-1-based drugs highly attractive for treating diabetes and obesity. To give a straightforward example, the GLP-1 receptor agonist Semaglutide, developed by Novo Nordisk, achieved sales exceeding 10 billion US dollars in 2022.

Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor. It can increase satiety, reduce appetite, and increase energy expenditure, thereby achieving better weight loss effects.

However, the GIP receptor has long not been considered a promising therapeutic target for metabolic diseases, with some even suggesting blocking it rather than activating it. Some industry experts speculate that the activation of the GIP receptor by tirzepatide might not be crucial, and perhaps it functions as a "super" GLP-1 receptor agonist to achieve better therapeutic effects.

So, is the actual situation really like this?

In this latest paper, the research team found that in mice, tirzepatide does indeed stimulate insulin secretion primarily by activating the GLP-1 receptor, but this is actually because the expression level of the GIP receptor in mice is relatively low.

In human islet cells, the GIP receptor is indispensable for insulin secretion when stimulated by tirzepatide. They also found that tirzepatide can stimulate the islets to secrete another hormone, glucagon. GIP stimulates glucagon secretion, while GLP-1 inhibits glucagon secretion. The discovery that tirzepatide stimulates glucagon secretion further demonstrates the significant activity of this drug on the GIP receptor.

This study shows that tirzepatide is a true dual receptor agonist, not just a super GLP-1 receptor agonist, which also validates the tremendous potential of using single molecules with multi-receptor activity as drugs for treating metabolic diseases.