About one in eight U.S. adults are currently taking a GLP-1 drug such as Ozempic, Wegovy, or Zepbound to treat diabetes, obesity, or other conditions, according to a KFF Health Tracking poll. But many suffer from significant side effects including nausea or vomiting. And for diabetic patients who also have conditions such as cancer or HIV, achieving glycemic control to effectively manage their blood sugar levels while avoiding weight or appetite loss is especially critical.
School of Nursing professor Bart de Jonghe studies ways to address debilitating side effects, while Perelman School of Medicine professor Matthew Hayes researches the signaling pathways that regulate food intake and body weight.
A new study from their labs, published in Diabetes, Obesity and Metabolism, shows that using a novel kind of agonist to target the GLP-1 receptor can preserve glycemic control while reducing malaise and vomiting behaviors in preclinical models. The compound uses a mechanism known as "biased agonism"—selectively activating certain signaling pathways to achieve desired effects without triggering others.
"[Biased agonism] gives us an opportunity here to create precision medicine," says Hayes, the Albert J. Stunkard Professor in Psychiatry. "The outcome is not going to be one-size-fits-all for GLP-1 pharmacotherapies."
When a GLP-1 agonist binds to its receptor, it can activate two main signaling pathways in the cell, explains lead author Caitlin Baumer-Harrison , a postdoctoral researcher in the Hayes and De Jonghe labs. One pathway produces cyclic adenosine monophosphate (cAMP), a key regulator of blood sugar. The other recruits β-arrestin, a protein that promotes receptor internalization—pulling the receptor into the cell, where it can be recycled or reused—and can trigger alternative signaling pathways.
The team found that the GLP-1 receptor agonist Exendin-4-Phe (Ex-Phe-1), a molecule created by researchers in the United Kingdom by substituting an amino acid in the GLP-1 receptor agonist Exendin-4, increases cAMP production but recruits less β-arrestin than standard GLP‑1 drugs, resulting in reduced side effects.
The researchers studied the effects of Ex-Phe-1 in three preclinical models. While the agonist maintained glycemic control in all of them, its effects on food intake and weight varied across species, as did the degree to which glycemic control was achieved compared with Ex-4.
The researchers note that these differences may reflect species-specific factors, including drug administration routes, dosing, and diets, as well as differences in tolerance or drug clearance rates. De Jonghe says studying the effects in multiple models is important as it prevents overgeneralizing findings.
Hayes says the researchers are next trying to understand why reduced β-arrestin recruitment may lessen nausea and vomiting more broadly—not just within the GLP-1 pathway. That insight could open new directions for drug development.
Bart C. De Jonghe is a professor of nutrition in the Department of Biobehavioral Health Sciences at the School of Nursing, with a secondary appointment in the Department of Psychiatry at the Perelman School of Medicine at the University of Pennsylvania.
Matthew R. Hayes is the Albert J. Stunkard Professor in Psychiatry, vice chair of basic and translational neuroscience, and director of the molecular and neural basis of psychiatric disease section in the Department of Psychiatry at Penn Medicine. He holds a secondary appointment at Penn Nursing.
Caitlin Baumer-Harrison is a postdoctoral researcher in the labs of Matthew R. Hayes and Bart C. De Jonghe.
The other authors are Brandon Alonso, Sarah V. Applebey, and Allison G. Xiao of Penn Medicine; Danya Aldaghma and Allaha Z. Mohiby of Penn Nursing; Tito Borner of Penn Medicine, Penn Nursing, and the University of Southern California; Minrong Ai, Matthew P. Coghlan, Tamer Coskun, Libbey S. O'Farrell, Yuewei Qian, Kyle W. Sloop, Alex D. White, and Francis S. Willard of Eli Lilly and Company; Robert P. Doyle of Syracuse University and State University of New York Upstate Medical University; and Allison M. Pataro of the University of Southern California.
This research was supported by the Diabetes Research Center in the Institute for Diabetes, Obesity & Metabolism at Penn Medicine (DK112812).
