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Unveiling Zepbound's Impact on the Brain and Pancreas: A Deep Dive into its Mechanisms

Innovative imaging method uncovers pancreas and brain mechanisms triggered by dual agonist medications like tirzepatide, regulating blood sugar levels and appetite.

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Zepbound Aims at the Brain and Pancreas: An Examination
Zepbound Aims at the Brain and Pancreas: An Examination

Unveiling Zepbound's Impact on the Brain and Pancreas: A Deep Dive into its Mechanisms

In a groundbreaking study published in the journal Nature Metabolism, a research group led by David Hodson at Oxford University has developed a novel imaging approach to investigate the effects of dual activators like Tirzepatide on the pancreas and brain.

The researchers, who also included scientists from the University of Leipzig and the University of Hamburg, created and tested daLUXendin and daLUXendin+, non-lipidated and lipidated fluorescent GLP1R/GIPR dual agonist probes. These probes were used to visualise the drug reaching regions involved in appetite regulation in the brain, including specialist cells known as tanycytes.

The study reveals that daLUXendins label rodent and human pancreatic islet cells, with a signal intensity of Ξ² cells > Ξ± cells = Ξ΄ cells. This finding suggests that the dual agonists' superior efficacy is not determined by improved access to the brain, as previously thought. Instead, the research raises new questions, such as what would happen if the drugs' access to the brain were improved.

Systemic administration of daLUXendin strongly labels GLP1R and GIPR neurons in circumventricular organs characterised by an incomplete blood-brain barrier. However, it does not penetrate the brain beyond labelling seen with single (ant)agonists. This finding suggests that the dual agonists' effects on the brain may be mediated through these specific organs.

The receptors form tiny clusters or 'nanodomains' in the pancreas, which may help explain how dual agonists amplify signals. The authors believe that this approach can be adapted to human studies and expanded to include other targets, such as new triple agonists that also act on glucagon receptors.

The next step will be to see how the results differ from those of triple agonists, which are more effective. The study provides valuable insights into why dual agonists are so successful and paves the way for further research into the mechanisms of these promising drugs.

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