How does tirzepatide stimulate insulin secretion?

Tirzepatide, a drug approved to treat diabetes and rapidly progressing toward approval as a weight-loss treatment, activates two different mechanisms the body uses to control insulin secretion and energy balance. It works through a unique ability, reports Duke Health researchers.

The discovery was reported in the journal June 5 natural metabolismis the first study to demonstrate, using cells from human donors, how tirzepatide stimulates insulin secretion, a key action utilized by the drug to lower blood sugar levels. type 2 diabetic.

“Understanding the potential of drugs to target multiple mechanisms opens up a whole new world of discoveries for better weight loss and diabetes drugs,” said lead author and associate professor in the Department of Medical Pharmacology. One Dr. Jonathan Campbell said: He majored in cancer biology at the Duke University School of Medicine and is a member of the Duke Institute of Molecular Physiology.

Tirzepatide is marketed under the trade name Mounjaro. Similar treatments are known as receptor agonists, which means they bind to specific receptors in cells and cause specific effects on those cells. Diabetes therapy targeting the glucagon-like peptide-1 (GLP-1) receptor has a long history.

For patients with type 2 diabetes, these GLP-1-based drugs restore insulin production and lower blood sugar levels. This treatment also causes people taking the drug to feel full longer and reduce their appetite, which leads to weight loss over time. This makes GLP-1-based therapies very attractive for the treatment of diabetes and obesity.

Tirzepatide is unique in this class of agents in that it targets not only the GLP-1 receptor, but also additional receptors for glucose-dependent insulinotropic polypeptide (GIP). Theoretically, this additional receptor could allow the drug to have a broader spectrum of activity in the body.

However, the GIP receptor has historically been neglected as a target for metabolic diseases, and some have even suggested blocking rather than activating this receptor. This history has led some experts to speculate that tirzepatide’s activity at the GIP receptor is immaterial and that tirzepatide functions as a ‘super’ GLP-1 receptor agonist.

Campbell et al. originally expected to find that most of tirzepatide’s activity is at the GLP-1 receptor. However, experiments with donated cadaveric islet cells show that the GIP receptor is essential for the insulin secretion that occurs when islets are stimulated with tirzepatide.

They also found that tirzepatide stimulates the production of another islet hormone, glucagon. GIP stimulates glucagon secretion, whereas GLP-1 inhibits glucagon secretion. The finding that tirzepatide stimulates glucagon secretion is further evidence that the drug has significant activity on her GIP receptor.

Our study shows that tirzepatide is not just a super-GLP-1 receptor agonist, but a true multi-receptor agonist, thus making it a viable approach to treat metabolic diseases with multiple We are testing the possibility of using single molecules with activity at the receptor. Extending these studies to cell types that control appetite and body weight should be an important and exciting future direction. “

Jonathan Campbell, Associate Professor of Medicine, Pharmacology and Cancer Biology, Duke University School of Medicine

In addition to Campbell, study authors include Kimberley El, Jonathan D. Douros, Francis S. Willard, Aaron Novikoff, Ashot Sargsyan, Diego Perez-Tilve, David B. Wainscott, Bin Yang, Alex Chen, Donald Wothe, and Callum Coupland. , and Matthias Chop, Brian Finnan, David A. D’Alessio, Kyle W. Sloop and Timo D. Muller.

This study was supported by the National Institute of Diabetes, Digestive and Kidney Diseases (K01 DK132461, R01 DK123075, DK125353, DK046492), the European Research Council (no.695054), the German Research Foundation (DFG TRR296, TRR152, SFB1123, and GRK 2816 /1), the German Center for Diabetes Research, the European Research Council (no.101044445), the Helmsley Charitable Trust Foundation, and investigator-led grants from Eli Lilly, Novo Nordisk, and Proteostasis.

Tilzepatide is manufactured by Eli Lilly and Company. The Campbell Group receives basic science funding from Novo Nordisk and Eli Lilly. Additional disclosures are permitted in this study.