Researchers led by Helmholtz Munich’s metabolic expert Professor Timo D. Müller have developed a new strategy to treat obesity and type 2 diabetes. Their approach uses specially designed hybrid molecules that utilize the well-known GLP-1/GIP signaling pathway as a type of entry point into cells. Once in the body, it delivers additional metabolic compounds directly to where they are needed.
In clinical tests, mice treated with the compound ate less, lost more weight, and showed better blood sugar control than mice treated with the standard comparison treatment. The results of this study were published in a journal as a preclinical study. nature.
Limitations of current GLP-1-based treatments
Modern incretin therapies that 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 further enhance these treatments. One goal is to add drugs that improve cells’ response to insulin, allowing glucose to move from the bloodstream to tissues more efficiently.
The challenge is that many of these additional drugs affect the entire body rather than specific target cells, increasing the potential for side effects. “Our guiding question was: How can we increase the activity of incretins without creating a second source of systemically active side effects?” said study director Timo D. Müller. says Timo D. Müller, director of the Institute of Diabetes and Obesity (IDO) in Munich, professor at the Ludwig Maximilians University of Munich (LMU), and researcher at the German Diabetes Research Center (DZD).
“Address label with cargo” design
To solve this problem, the team designed what they describe as “consignment address labels.” They chemically combined a known incretin-based compound with a second drug called ranifibranol, a pan-PPAR agonist.
The incretin moiety binds to GLP-1 or GIP receptors on the cell surface, allowing entry of the hybrid molecule. Once inside, the second component activates PPARs. PPARs act as “switches” in the cell nucleus that control genes involved in fat and sugar metabolism. This design aims to focus the added metabolic effects on GLP-1R/GIPR-expressing cells rather than dispersing them throughout the body.
“Trojan” delivers low doses
Functionally, this 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. Muller likens this concept to a “Trojan horse.” The incretin component opens the door, and additional drugs act only after entering the cell.
“The big advantage is the money,” Muller said. “Because the second component travels together with the incretin moiety, rather than being administered systemically separately, it can be used at orders of magnitude lower doses.” This targeted delivery could improve efficacy while limiting side effects associated with widespread drug exposure.
Strong weight loss and effects on blood sugar levels in mice
In mice with diet-induced obesity, the hybrid drug had clear effects. “Animals ate less and lost more weight than when given the non-cargo GLP-1/GIP co-agonist,” said Dr. Daniela Liskiwicz, IDO group leader and co-lead author with Dr. Aaron Novikov. “In the head-to-head comparisons shown, the effects were in part even stronger than GLP-1-only drugs.”
These results suggest that this approach does more than simply add another mechanism. Rather, it appears to enhance the overall efficacy of incretin therapy, at least in animal models.
Improved metabolism and safety signals
This treatment wasn’t just about losing weight. The mice also showed signs of improved blood sugar levels and improved insulin function. Simply put, insulin is more effective at moving glucose from the bloodstream to the tissues, and the liver releases less glucose into the circulation.
The researchers also observed that common gastrointestinal side effects were similar to those seen with current incretin drugs. Importantly, no signs of fluid retention or anemia were detected, which are known concerns with added drug components.
Early discovery with potential beyond weight loss
This data also suggests possible benefits for heart and liver health. However, the researchers stress that these findings come from preclinical studies. It remains unclear whether the same results would occur in humans, especially since GIP receptors differ between mice and humans.
“We have identified the principles behind the powerful effects in animal models, and the challenge now is to optimize the approach for humans and translate it to the clinic,” says Müller. He notes that moving forward with this effort requires collaboration with industry partners.
About the researcher
Professor Timo D. Müller is Director of the Institute for Diabetes and Obesity (IDO) at the Helmholtz München, Professor at the Ludwig-Maximilians-University of Munich (LMU) and researcher at the German Diabetes Research Center (DZD).
