How Dual and Triple Agonists Like Tirzepatide Work Inside Pancreatic Cells | Research

The takeaway

Dual and triple receptor agonists that target GLP-1, GIP, and glucagon receptors simultaneously show strong clinical results for diabetes, but scientists still don't fully understand how activating multiple receptors at once changes cell signaling.

3 receptors, 1 molecule
Triple agonists simultaneously activate GLP-1, GIP, and glucagon receptors — and the glucagon benefit was unexpected, since glucagon normally raises blood sugar.

What the researchers found

Clinical studies of dual GLP-1/GIP receptor agonists (unimolecular dual-receptor agonists or UDRAs) have demonstrated favorable results both as standalone treatments and in combination with other diabetes drugs. The additive insulin-boosting effects of dual GLP-1 and GIP receptor activation were expected based on what each hormone does individually.

However, the additional benefits from adding glucagon receptor (GCGR) activation in triple agonists were largely unexpected, since glucagon normally raises blood sugar. Whether simultaneous stimulation of these three receptor pathways creates synergistic or antagonistic interactions at the cellular level remains unknown and requires further investigation.

Why it matters

Drugs like tirzepatide (a dual GLP-1/GIP agonist) and retatrutide (a triple agonist) represent a major shift in diabetes and obesity treatment. Understanding exactly how these drugs work at the cellular level is essential for predicting long-term safety, optimizing dosing, and designing even better multi-agonist peptides. The finding that glucagon receptor activation provides unexpected benefits challenges conventional thinking about diabetes treatment.

How the study worked

This was a scoping review examining the published literature on the cellular mechanisms of action of dual- and triple-receptor agonist peptides in pancreatic islet cells. The authors analyzed studies covering the signaling pathways activated by GLP-1, GIP, and glucagon receptors individually and in combination, drawing on both preclinical mechanistic studies and clinical efficacy trials.

What this study cannot tell us

As a scoping review, this paper maps the current state of knowledge rather than providing new experimental data. The authors acknowledge that the signaling pathway interactions from simultaneous dual and triple receptor stimulation require much deeper investigation. Most mechanistic understanding comes from studying each receptor pathway individually, which may not capture the complexity of simultaneous activation.

How to read the evidence

This is a scoping review that synthesizes existing mechanistic and clinical literature rather than presenting original data. While it references clinical trial results, its primary contribution is conceptual — mapping knowledge gaps in multi-receptor agonist signaling.

When this study was published

Published in 2023, this review covers the state of multi-agonist peptide research through 2023. The field is evolving rapidly with ongoing phase III trials for retatrutide and other triple agonists, so new mechanistic insights may have emerged since publication.

The bigger picture

Multi-agonist peptides are the hottest area in metabolic drug development. Tirzepatide's dual agonism produced unprecedented weight loss and blood sugar control, and triple agonists like retatrutide are pushing results even further. This review highlights an important gap: these drugs are already in patients' hands, but the scientific understanding of how simultaneous multi-receptor activation works at the cellular level is still catching up to the clinical results.

Questions still open

Do the three receptor pathways (GLP-1, GIP, glucagon) interact synergistically inside cells, or do some effects cancel each other out?
Why does glucagon receptor activation — which normally raises blood sugar — provide metabolic benefits when combined with GLP-1 and GIP agonism?
Could understanding the combined signaling pathways reveal new safety concerns not apparent from studying each receptor alone?

Common questions

What's the difference between a dual agonist and a triple agonist for diabetes?

A dual agonist like tirzepatide activates two hormone receptors at once (GLP-1 and GIP), both of which boost insulin release and reduce appetite. A triple agonist adds glucagon receptor activation on top of that. Counterintuitively, activating the glucagon receptor — which normally raises blood sugar — appears to provide additional metabolic benefits, possibly by increasing energy expenditure and fat burning.

If these drugs work so well clinically, why does it matter that scientists don't fully understand the mechanism?

Understanding how a drug works at the cellular level is critical for predicting long-term safety, identifying who will respond best, and designing improved versions. When multiple receptor pathways are activated simultaneously, unexpected interactions could emerge over years of use that wouldn't be apparent in short-term trials.

Read the original research

Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets.

American journal of physiology. Endocrinology and metabolism, 325(5), E595-E609

View on PubMed ↗Publisher’s paper ↗

Citation

Folli, Franco; Finzi, Giovanna; Manfrini, Roberto; Galli, Alessandra; Casiraghi, Francesca; Centofanti, Lucia; Berra, Cesare; Fiorina, Paolo; Davalli, Alberto; La Rosa, Stefano; Perego, Carla; Higgins, Paul B. (2023). Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets.. American journal of physiology. Endocrinology and metabolism, 325(5), E595-E609. https://doi.org/10.1152/ajpendo.00236.2023