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A team led by metabolism researcher Prof Timo D. Müller at Helmholtz Munich has developed a new approach for treating obesity and type 2 diabetes: a hybrid molecule uses the well-known GLP-1/GIP signalling pathway as a “door opener” and delivers an additional metabolic modulator specifically into the target cells. In laboratory experiments, mice subsequently ate less, lost more weight and showed improved blood-glucose values compared with reference treatments. The researchers published their preclinical results in the journal Nature.
Modern incretin therapies – drugs that mimic the body’s own satiety and blood-glucose signals (GLP-1/GIP) – have markedly improved the treatment of obesity and type 2 diabetes. Yet a key challenge remains: physicians would like to use further metabolic “levers”, for example drugs that make cells more responsive to insulin, so that glucose moves more easily from the blood into tissues. However, such additional drugs often act system-wide rather than in a targeted manner, increasing the risk of side effects. “Our guiding question was: how can we enhance incretin activity without creating a second, systemically active source of side effects?” says the study lead Timo D. Müller, Director of the Institute for Diabetes and Obesity (IDO) at Helmholtz Munich, Professor at the Ludwig Maximilian University of Munich (LMU) and researcher at the German Center for Diabetes Research (DZD).
Müller’s team therefore pursued the idea of an “address label with cargo”: the researchers chemically linked a well-established incretin active component to a second pharmacological component – the drug lanifibranor, a so-called pan-PPAR agonist. The incretin part binds to GLP-1 or GIP receptors on the cell surface and ensures that the hybrid molecule is taken up into the cell. Inside the cell, the second component binds to PPARs – “switches” in the cell nucleus that regulate genes involved in fat and sugar metabolism. The aim is for this additional metabolic effect to arise specifically in GLP-1R/GIPR- expressing cells, rather than throughout the body.
Low Dose via a “Trojan Horse”
Functionally, the hybrid molecule combines five drug targets in one: it activates two receptors on the cell surface (GLP-1R and GIPR) and additionally engages three PPAR “switches” inside the cell. Müller describes the principle as a “Trojan horse”: the incretin part opens the door; the “cargo” acts only once it is inside the target cell. “A major advantage is the amount,” says Müller. “Because the second component is not administered separately and systemically, but ‘travels along’ with the incretin part, it can be used at a dose that is orders of magnitude lower.” In this way, the drug gains efficacy without amplifying side effects through broad distribution across the body.
In laboratory mice with diet-induced obesity, the approach showed clear effects: “The animals ate less and lost more weight than under a GLP-1/GIP co-agonist without cargo,” says Dr Daniela Liskiewicz, group leader at IDO and co-first author together with Dr Aaron Novikoff. “In the head-to-head comparisons shown, the effect was in part even stronger than with a GLP-1-only drug.” The study therefore suggests that the coupling is not merely “more of the same”, but measurably strengthens incretin activity – at least in mice.
Additional Metabolic Readouts Improve
It was not only body weight that changed: in the experiments, blood-glucose values improved and there were indications of better insulin action in the body. Put simply, insulin was better able to “channel” glucose from the blood into tissues, and the liver released less glucose into the bloodstream. At the same time, the researchers report that typical gastrointestinal side effects were comparable in their assessment to those of existing incretin therapies – and that, in the parameters examined, they found no indications of two feared issues associated with the coupled component, namely fluid retention and anaemia.
Beyond glucose metabolism, the mouse data also provided indications of additional, potentially favourable effects on the heart and liver. It is important to note that this is a preclinical study: whether the results will translate to humans remains open – also because the GIP receptor differs between mice and humans. “We see a principle with strong effects in the animal model – now the task is to optimise the approach for humans and move it towards the clinic,” says Müller. For that development, strong industry partners will be needed, he adds.
About the Researcher
Prof. Timo D. Müller, Director of the Institute for Diabetes and Obesity (IDO) at Helmholtz Munich, Professor at the Ludwig Maximilian University of Munich (LMU) and researcher at the German Center for Diabetes Research (DZD).
About Helmholtz Munich
Helmholtz Munich is a leading biomedical research center. Its mission is to develop breakthrough solutions for better health in a rapidly changing world. Interdisciplinary research teams focus on environmentally triggered diseases, especially the therapy and prevention of diabetes, obesity, allergies, and chronic lung diseases. With the power of artificial intelligence and bioengineering, researchers accelerate the translation to patients. Helmholtz Munich has more than 2,550 employees and is headquartered in Munich/Neuherberg. It is a member of the Helmholtz Association, with more than 46,000 employees and 18 research centers the largest scientific organization in Germany. More about Helmholtz Munich (Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH): www.helmholtz-munich.de/en
Liskiewicz et al., 2026: A unimolecular GIPR:GLP-1R:PPAR𝛼,𝛾,𝛿 quintuple agonist eliminates obesity and insulin resistance in mice. Nature. DOI: 10.1038/s41586-026-10427-5
https://www.helmholtz-munich.de/en/newsroom/news-all/artikel/timo-mueller-receiv...
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