Shane Wright, Assistant Professor at the Department of Physiology and Pharmacology, and colleagues have uncovered a new way to tailor signaling responses mediated by common drug targets that coincidentally shares ties with our department's history. The work, recently published in Cell, reveals a novel drug mechanism with the potential for treating type 2 diabetes and obesity. Shane tells us more about it below.
KI press release on the Cell article: New drug for diabetes and obesity shows promising results
Nearly 80 years ago, Ulf von Euler discovered norepinephrine while working at the Department of Physiology and Pharmacology (then Dept. of Physiology), Karolinska Institutet. Norepinephrine, also known as noradrenaline, is an important neurotransmitter that he determined was involved in the fight-or-flight response. Ulf von Euler would later win the Nobel Prize in Physiology or Medicine in 1970 for these seminal discoveries.
We have learned a lot over the last 80 years building on Ulf von Euler's discoveries. Now it is well-established that norepinephrine is a multifunctional neurotransmitter binding numerous receptors including the beta-2 adrenergic receptor. The binding of norepinephrine to the beta-2 receptor leads to the engagement of the stimulatory G protein promoting cyclic AMP accumulation. This action has enormous benefits for hypotensive patients in the intensive care unit, but molecules that behave like norepinephrine can have negative effects on the heart. When given systemically over sustained periods, they can cause the heart to work too hard leading to cardiovascular problems. For patients that suffer from hypertension, blocking this action has proven beneficial and led to the widespread prescription of drugs called beta blockers.
Beyond its function in the heart, activation of beta-2 receptors present in the skeletal muscle mediates glucose uptake which effectively lowers blood glucose levels. From a drug development perspective, it would make sense to exploit this property of skeletal muscle-localized beta-2 receptors to make a treatment for type 2 diabetes. However, molecules like norepinephrine that stimulate cAMP production would not be suitable to give patients long-term because of the aforementioned consequences to the heart.
What if a drug could be made that looked like norepinephrine, but promoted glucose uptake without cAMP production? Would it be possible to direct the beta-2 receptor to select one outcome over another and how would that be achieved?
This was the dream that brought researchers from FyFa and Stockholm University together. It was a common interest in receptors that prompted Assistant Professor Shane Wright from the department and Professor Tore Bengtson from SU to join forces. Shane had been working on understanding how G protein-coupled receptors like the beta-2 are able to mediate different effects in the body. Tore had been tirelessly optimizing norepinephrine-like molecules that would promote glucose uptake (beneficial effect) without cAMP accumulation (side effect).
G protein-coupled receptors (GPCRs) are the largest family of receptors in the human body and happen to represent the target of 36% of drugs on the market. They have been known for many years to signal through the proteins that gave them their name - the heterotrimeric G proteins - but in addition to this, they have been shown to recruit and signal through scaffolding proteins known as β-arrestins. Since the 80s, researchers have been examining the balance in signaling through these two proteins called transducers. In some instances, it can be appropriate to shift this balance between G proteins and β-arrestins to avoid the negative effects associated with one or the other. These findings have fueled a new type of drug discovery built on "biased agonism." In essence, this principle aims to tailor signaling pathways to achieve the appropriate outcome; ultimately minimizing adverse outcomes.
With the help of some talented chemists, Tore founded Atrogi AB on the Solna campus at KI to find new molecules for the beta-2 receptor that would have "made-to-fit" signaling pathways to achieve efficacy in type 2 diabetes without side effects. The chemistry campaign turned out to be a huge success revealing that it was indeed possible to develop molecules that bind the beta-2 in a new way promoting glucose uptake with minimal cAMP production. The question was how did this work mechanistically and would this in any way be translatable?
As mentioned previously, GPCRs bind to G proteins and β-arrestins. This recruitment has historically been seen as sequential (i.e., first G proteins and then arrestins) and facilitated by a small family of kinases called G protein-coupled receptor kinases (GRKs). These kinases are recruited to the receptor following G protein activation to phosphorylate the receptor and promote the subsequent high affinity binding of arrestins. Aside from this role in receptor phosphorylation, GRK recruitment and activation by GPCRs has not been viewed as a signaling module on its own that can be exploited for patient benefit.
Having put together a molecular toolbox capable of measuring nearly 20 pathways downstream of these receptors, Shane began some detective work to find out how these molecules were activating the beta-2 receptor differently, together with a very talented PhD student, Aikaterini Motso, who was supervised by both Shane and Tore. The results were surprising. They had found that these molecules were capable of stimulating GRK recruitment with very little binding of G proteins and β-arrestins.
In animal studies, several of the developed molecules were shown to have good effects on both blood sugar control and body composition, but without the side effects associated with today's widely prescribed GLP-1-based drugs that are known to have gastrointestinal side effects and reduce muscle mass. An initial phase I clinical trial involving 48 healthy subjects and 25 people with type 2 diabetes showed that the treatment was well tolerated in humans.
Following these encouraging results, the next step is a larger, phase II clinical study planned by Atrogi AB, the company developing the treatment. The aim of the study is to see whether the same positive effects seen in preclinical models also occur in people with type 2 diabetes or obesity.
This discovery is groundbreaking because it expands the realm of possibilities for how GPCRs can be targeted in the future and has important implications beyond beta-2 receptors and type 2 diabetes. Nearly 80 years since Ulf von Euler discovered norepinephrine, there is still so much more to learn about receptor pharmacology and many opportunities for drug discovery.
The study is the result of close collaboration with Professor Volker M. Lauschke from FyFa and other researchers at Karolinska Institutet, Stockholm University, and Uppsala University in Sweden, the University of Copenhagen in Denmark, and Monash University and the University of Queensland in Australia. The research was funded by the Swedish Research Council, the Swedish Society for Medical Research, and the Novo Nordisk Foundation, among others.
Publication: "GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity," Aikaterini Motso, Benjamin Pelcman, Anastasia Kalinovich, Nour Aldin Kahlous, Muhammad Hamza Bokhari, Nodi Dehvari, Carina Halleskog, Erik Waara, Jasper de Jong, Elizabeth Cheesman, Christine Kallenberg, Gopala Krishna Yakala, Praerona Murad, Erika Wetterdal, Pia Andersson, Sten van Beek, Anna Sandström, Diane Natacha Alleluia, Emanuela Talamonti, Sonia Youhanna, Pierre Sabatier, Claire Koenig, Sabine Willems, Aurino M. Kemas, Dana S. Hutchinson, Seungmin Ham, Lukas Grätz, Jan Voss, Jose G. Marchan-Alvarez, Martins Priede, Krista Jaunsleine, Jana Spura, Vadims Kovada, Linda Supe, Leigh A. Stoddart, Nicholas D. Holliday, Phillip T. Newton, Nicolas J. Pillon, Gunnar Schulte, Roger J. Summers, Ilga Mutule, Edgars Suna, Jesper V. Olsen, Peter Molenaar, Jens Carlsson, Volker M. Lauschke, Shane C. Wright & Tore Bengtsson, Cell, online June 23, 2025, doi: 10.1016/j.cell.2025.05.042.
