Researchers led by metabolism expert Prof Timo D. Müller at Helmholtz Munich have developed a new strategy to treat obesity and type 2 diabetes. Their approach uses a specially designed hybrid molecule that takes advantage of the well-known GLP-1/GIP signalling pathway as a kind of entry point into cells. Once inside, it delivers an additional metabolic compound directly where it is needed.
In laboratory tests, mice treated with this compound ate less food, lost more weight, and showed better blood-glucose control than those given standard comparison treatments. The findings were published as a preclinical study in the journal Nature.
Limits of Current GLP-1-Based Therapies
Modern incretin therapies, which mimic natural satiety and blood sugar signals (GLP-1/GIP), have significantly improved treatment options for obesity and type 2 diabetes. Still, researchers are looking for ways to enhance these therapies further. One goal is to add drugs that improve how cells respond to insulin, helping glucose move more efficiently from the bloodstream into tissues.
The challenge is that many of these additional drugs affect the entire body rather than specific target cells, raising the likelihood 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).
“Address Label With Cargo” Design
To solve this problem, the team designed what they describe as an “address label with cargo.” They chemically combined a known incretin-based compound with a second drug called lanifibranor, a pan-PPAR agonist.
The incretin portion binds to GLP-1 or GIP receptors on the surface of cells, allowing the hybrid molecule to enter. Once inside, the second component activates PPARs, which act as “switches” in the cell nucleus that control genes involved in fat and sugar metabolism. This design is intended to concentrate the added metabolic effect in GLP-1R/GIPR- expressing cells instead of distributing it throughout the body.
A “Trojan Horse” Delivers a Low Dose
Functionally, the molecule targets five pathways at once. It activates two receptors on the cell surface (GLP-1R and GIPR) and also engages three PPAR “switches” within the cell. Müller compares the concept to a “Trojan horse”: the incretin component opens the door, and the additional drug acts only after entering the 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.” This targeted delivery may improve effectiveness while limiting side effects linked to widespread drug exposure.
Strong Weight Loss and Blood Sugar Effects in Mice
In mice with diet-induced obesity, the hybrid drug produced clear benefits. “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.”
These results suggest the approach does more than simply add another mechanism. Instead, it appears to enhance the overall effect of incretin therapy, at least in animal models.
Improved Metabolism and Safety Signals
The treatment did more than reduce body weight. Mice also showed improved blood-glucose levels and signs of better insulin function. In simple terms, insulin was more effective at moving glucose from the bloodstream into tissues, and the liver released less glucose into circulation.
The researchers also observed that common gastrointestinal side effects were similar to those seen with current incretin drugs. Importantly, they did not detect signs of fluid retention or anemia, which are known concerns with the added drug component.
Early Findings With Potential Beyond Weight Loss
The data also hinted at possible benefits for heart and liver health. However, the researchers stress that these findings come from a preclinical study. It remains uncertain whether the same results will occur in humans, especially since the GIP receptor differs between mice and people.
“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. He notes that advancing this work will require collaboration with industry partners.
About the Researcher
Prof. Timo D. Müller is Director of the Institute for Diabetes and Obesity (IDO) at Helmholtz Munich, Professor at the Ludwig Maximilian University of Munich (LMU), and a researcher at the German Center for Diabetes Research (DZD).