An international study with the participation of the Leibniz Research Institute for Molecular Pharmacology (FMP) in Berlin has made groundbreaking progress in the research of modern diabetes and obesity drugs. With the help of novel fluorescent markers, it was made visible for the first time how the drug tirzepatide travels through the body and brain and which target cells it addresses. The findings, published in the journal Nature Metabolism, open up new perspectives for improving therapies for diabetes and obesity.

Tirzepatide, known by the trade names Mounjaro and Zepbound, is a dual agonist that binds to GLP-1 and GIP receptors at the same time. These receptors, found in the pancreas and brain, promote insulin release after meals and regulate appetite and metabolism. While the effect of tirzepatide on blood sugar and body weight is well documented, it was previously unclear which specific cells the drug activates. A team of researchers led by Johannes Broichhagen (FMP), David Hodson (University of Oxford) and Anne de Bray (University of Birmingham) developed fluorescent markers, so-called daLUXendins, that close this gap.

The daLUXendins enable the visualization of GLP-1 and GIP receptors in living cells and tissues. The scientists were thus able to prove that tirzepatide binds primarily to beta cells, but also to alpha and delta cells in the pancreas. In the brain, the drug activates specific nerve cells and tanycytes that are crucial for appetite control and metabolism. The discovery of receptor clusters in islet cells, which became visible by super-resolution microscopy, was particularly revealing. These clusters could explain why dual agonists such as tirzepatide are particularly effective.

The study shows that the markers not only reveal the sites of action of tirzepatide, but also help to understand the dynamics of the signaling pathways. This could make future therapies more precise, for example by specifically improving access to drugs into the brain. However, the study has limitations: The investigations were mainly based on mouse models, and the markers are not identical to tirzepatide. Further research is needed to transfer the results to humans and to expand the color palette of the markers.

The findings underline the importance of dual agonists and at the same time raise new questions, such as the effect of triple agonists with glucagon content. The study marks an important step towards optimized treatments for diabetes and obesity, the prevalence of which has risen sharply since the 1980s, according to the WHO.

Original Paper:

Fluorescent GLP1R/GIPR dual agonist probes reveal cell targets in the pancreas and brain | Nature Metabolism

Editor: X-Press Journalistenbüro GbR

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