Sister hormone of GLP-1 could lead to better weight-loss drugs

Much like the Cold War space race, the world's pharmaceutical giants are currently scrambling to produce the best weight-loss drug. They all want to be the first to explore the nooks and crannies of the body in order to be able to design the optimal drug. However, several pharmaceutical giants disagree on what the next step should be.

The kernel of the controversy is the GIP hormone—a sister hormone of the well-known GLP-1 hormone on which Wegovy is based.

While some pharmaceutical giants argue that weight-loss drugs should activate the GIP hormone for optimum effect, others believe it should be inhibited, as tests with currently available weight-loss drugs have resulted in effective weight loss both when the GIP receptor is activated and when it is inhibited.

Now a fundamental research project from the University of Copenhagen sheds light on the matter.

The leading authors of the new study are Professor Mette Rosenkilde, who is head of the Molecular Pharmacology Laboratory, Associate Professor Niels Grarup, who is head of a group focusing on genetic research at the Novo Nordisk Foundation Center for Basic Metabolic Research, and Associate Professor Alexander Hauser, who is head of a group focusing on pharmaceutical informatics at the Faculty of Health and Medical Sciences.

"There is untapped potential in exploring how the GIP receptor works and how we can utilize this to design new drugs, and our study brings us a step closer to tapping into this potential," says Rosenkilde.

Data from the study shows that inhibiting the GIP receptor may result in weight loss. The way the GIP receptor is inhibited and activated is of paramount importance, though, she explains.

"Signaling regulation is more sophisticated in GIP than GLP-1. Here, its ability to bind arrestins is vital. Arrestins are a group of molecules that serve to block the GIP signal," adds Rosenkilde.

The results of the study are based on a data survey involving more than 500,000 individuals, 10,000 of which are Danish citizens who have participated in a national research project, while the rest have been harvested from the UK Biobank.

"We did a series of clinical tests among the Danish population, e.g. blood tests and recordings of weight and height, and then we identified congenital GIP receptor variations in the test subjects by sequencing their genes," says Assistant Professor Niels Grarup from the Novo Nordisk Center for Basic Metabolic Research, who has extensive experience with studying genetic variations associated with type 2 diabetes.

"Based on the Danish data, we analyzed a large number of individuals from the UK Biobank to see if we would find the same tendency," says Associate Professor Alexander Sebastian Hauser from the Department of Drug Design and Pharmacology, who focuses on pharmacogenomics and pharmaceutical data science.

In addition, the researchers conducted mice and cell studies and compared the results to the results of the Danish and UK Biobank data surveys

The vomiting center

GLP-1 and GIP serve the same fundamental function: to regulate the insulin level in the body when we eat. But that is not all they do, it turns out.

"GLP-1 plays a role in the digestive system as well as the brain. So it makes sense to think that the sister hormone, GIP, could have the same potential," says Rosenkilde.

And there is evidence to suggest that this is indeed the case. Hauser explains, "The GIP receptor undoubtedly affects the brain, where it helps regulate the vomiting center. Generally, this family of receptors plays a vital role in the brain—both during normal brain function and during disease."

Therefore, a weight-loss drug combining GIP and GLP-1 could be particularly effective without causing nausea, which is a common side effect of weight-loss drugs, Rosenkilde explains. She stresses, "The new study gives us a fundamental understanding of how this receptor works in healthy bodies, and I hope this knowledge will prove useful in the design of new drugs."

Read the full study, "Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes," in Nature Metabolism.