Interview with Prof. Timo Müller
A Key with Many Teeth: How Many Biological Signals Are Shaping New Therapies for Obesity and Diabetes
Modern drugs for obesity and type 2 diabetes are based on a simple insight: metabolic pathways are not controlled by a single signal, but by many acting together.
Prof. Timo D. Müller is Director of the Institute for Diabetes and Obesity (IDO) at Helmholtz Munich and Professor at the Ludwig Maximilians University of Munich (LMU). Together with his team, he investigates how these biological mechanisms can be harnessed therapeutically – from GLP-1-based drugs to new hybrid molecules that deliver additional active components directly into specific cells.
Modern drugs for obesity and type 2 diabetes are based on a simple insight: metabolic pathways are not controlled by a single signal, but by many acting together.
Prof. Timo D. Müller is Director of the Institute for Diabetes and Obesity (IDO) at Helmholtz Munich and Professor at the Ludwig Maximilians University of Munich (LMU). Together with his team, he investigates how these biological mechanisms can be harnessed therapeutically – from GLP-1-based drugs to new hybrid molecules that deliver additional active components directly into specific cells.
Prof. Müller, so-called “weight-loss injections” have become increasingly prominent in public debate in recent years. Your research focuses on the biological mechanisms behind such drugs – but goes far beyond weight loss. What is the core of your work?
At its core, our work is about better understanding how the body regulates hunger and satiety, and how this affects body weight and blood sugar. The brain does not rely on a single signal, but on a whole range of information coming from the periphery – for example from the gut, fat tissue, liver, or pancreas. We aim to make these signaling mechanisms therapeutically useful. That is why we develop drugs for obesity and diabetes that do not activate just a single receptor, but combine several mechanisms within one molecule.
Many people now know GLP-1 mainly as the basis of modern weight-loss drugs. What is the natural function of this hormone – and how did it become therapeutically useful?
First of all, GLP-1 is not a “weight-loss hormone.” It is a natural gut hormone that is released after eating and signals to the pancreas: there is sugar in the blood, please release insulin. So its natural primary role is blood sugar regulation.
The fact that GLP-1-based drugs can also reduce body weight is a pharmacological extension of this natural function. To achieve that, the molecule first had to be modified so that it would remain in the body long enough. It was only with long-acting GLP-1 mimetics that this signaling pathway could be used broadly in therapy – first for type 2 diabetes, and later for obesity.
GLP-1 and GIP: Key Gut Hormones in Metabolism
GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) are gut hormones released after eating that help regulate metabolism. GLP-1 boosts insulin release, lowers blood sugar, slows stomach emptying, and reduces appetite, while GIP also supports insulin secretion and plays a role in energy balance. Together, they are key targets for modern treatments of type 2 diabetes and obesity.
If GLP-1 works, why did you want to go further?
We asked ourselves whether it really makes sense to strongly activate just one signaling pathway. After all, the body does not regulate hunger and satiety through a single hormone, but through many signals at the same time. The brain continuously evaluates the totality of all this information. You can think of it like a key: it does not have just one tooth, but many. It is the overall pattern that determines whether it fits the lock. In the body, it is the overall pattern of hormones that determines how the brain responds.
That led to the idea of using one molecule to target not just one mechanism, but several. These so-called polyagonists are designed to activate different metabolic pathways in parallel. The advantage is that you do not have to stimulate one receptor more and more strongly – which can quickly lead to side effects, but can instead combine several smaller effects that together become more powerful.
How did the idea of polyagonists emerge – and what role did you and your team play in it?
It was a longer process of development. The basic idea was shaped decisively by Prof. Richard DiMarchi and Prof. Matthias Tschöp. In a collaborative effort with Tschöp and DiMarchi, my team and I then spent many years further developing the concept from a biological and mechanistic perspective.
What Is a Polyagonist?
A polyagonist is a drug that activates more than one receptor in the body at the same time. A GLP-1/GIP polyagonist, for example, targets both the GLP-1 and GIP receptors, allowing it to influence several metabolic processes simultaneously, including blood sugar control, insulin release, and appetite regulation.
How has this concept evolved in your current work?
At first, the idea was to combine several metabolic signals within one molecule in order to better balance efficacy and tolerability. In our current work, we take this one step further: we use such hybrid agents not only to target several signaling pathways at once, but also to deliver additional active components directly into the key target cells. The second component no longer has to distribute freely throughout the body. We can deliver it very precisely to its destination – and that means an extremely low dose is sufficient.
What does that look like in practice?
We have just published a paper in Nature. In it, we describe how we linked a known GLP-1/GIP co-agonist to a second active component – in this case lanifibranor, a compound that influences important metabolic programs in the cell nucleus. The GLP-1/GIP part binds to the relevant target cells and is taken up into the cell together with its additional cargo, almost piggyback. Inside the cell, the second component is released and can act exactly where it is needed.
You can think of it like a Trojan horse: the co-agonist brings the cargo specifically to its site of action and smuggles it in. The key advantage is that we no longer have to distribute this additional component broadly throughout the body. As a result, very small amounts are enough.
How did this advantage show up in your experiments?
In the mouse model, the hybrid molecule was clearly superior to the GLP-1/GIP co-agonist alone. The animals ate less, lost more weight, and showed better blood sugar control. We also saw indications of improved insulin action as well as favorable effects on the heart and liver. But what was also important for us was this: we did not see any indication that typical gastrointestinal side effects became worse. And we did not observe two feared problems associated with the additional component – fluid retention and anemia – in our paper either.
Looking back, it almost sounds straightforward. Was the path really that clear?
No, not at all. In hindsight, research often appears much more linear than it actually is. For every concept that works, there are many variants that do not work or are not strong enough therapeutically. That was true for us as well: we tested different molecules, linkers, and combinations. Research in this field always involves fine-tuning.
Your work is in the preclinical field. What are the biggest hurdles on the path to the clinic?
The biggest challenge is always translation to humans. Mouse models are enormously important for understanding mechanisms and testing new concepts. But humans are different. In our field in particular, individual receptor systems and their physiological relevance can differ quite substantially between mice and humans. So even with our current hybrid molecule, one thing is clear: the results in the animal model are very promising, but the approach still has to be further optimized for humans.
You have worked intensively on GLP-1 and GIP for years. What has surprised you most?
What was particularly exciting for us was the role of GIP. For a long time, there were many indications that this pathway should rather be blocked. But our work showed that, under the right conditions, activating the GIP receptor can also contribute substantially to weight reduction. Even more interestingly, both activation and blockade of the GIP receptor can reduce body weight – albeit through different mechanisms in the brain. For us, that was an important indication of just how complex this signal processing really is.
What role does the brain play in this?
A central one. We were able to show that certain drugs act not only in the body, but also through specific neuronal circuits that regulate food intake and energy balance. For me, that has always been a key part of our work: not just seeing that a molecule works, but understanding through which cells and mechanisms that effect is mediated.
These new drugs are often discussed as “weight-loss injections.” Is medicine here repairing something that is going wrong elsewhere in society?
Obesity is a disease, not a question of lacking discipline. People with obesity have an increased risk of type 2 diabetes, cardiovascular disease, fatty liver disease, and many other secondary conditions. Treating these patients medically is therefore not a lifestyle issue, but a matter of healthcare.
Of course, we live in an environment that promotes weight gain. But that does not mean that those affected are to blame. What we are dealing with here is a disorder of metabolic regulation – and that is exactly where our therapies intervene.
Where do you think the field will be heading in the coming years?
The next generation of drugs will become even more precise. We will continue trying to better balance efficacy and tolerability, while reducing typical side effects. In the long term, the goal is to make metabolic therapies not just stronger, but smarter: through better biological understanding, more precise molecules, and increasingly targeted engagement of the relevant cell types.
And personally: is this the theme that defines your scientific career?
Yes, very clearly. You do not develop concepts like these many times in a lifetime. The work on polyagonists and targeted peptide conjugates has strongly shaped my research over the past years – and it will certainly continue to occupy me in the future.
Prof. Timo Müller is Director of the Institute for Diabetes and Obesity (IDO) at Helmholtz Munich and Professor at the Medical Faculty of the Ludwig Maximilian University of Munich. He is widely recognized as a global leader in metabolic research, driving transformative advances in diabetes science and metabolic medicine. His work has been honored with numerous prestigious awards, including the 2026 ADA Outstanding Scientific Achievement Award, the Minkowski Prize awarded by the European Association for the Study of Diabetes (2023), the Werner-Creutzfeldt Award of the German Diabetes Association (2023), and the Galenus von Pergamon Prize (2022). In 2023, Science named GLP-1–based therapies the Breakthrough of the Year.
