Sinai Health study identifies new concepts for GLP-1 action in the brain, the 2023 Science magazine breakthrough of the year

Not only have millions of people with type 2 diabetes benefitted from GLP-1 agonists, but the drugs also produced wide-ranging health benefits beyond weight loss in two recent patient trials.
For years, GLP-1 agonists have been known to have a fortuitous side effect of improving metabolic health, but how this is regulated in the body remains unclear. Now Dr. Drucker, who has dedicated his life’s work to understanding how these drugs work, has a new paper that begins to unravel the mystery with a novel finding – it all starts in the brain.

His team at the Lunenfeld-Tanenbaum Research Institute, part of Sinai Health, have discovered a gut-brain-immune network that controls inflammation across the body affecting organ health, in a project led by postdoctoral scientist Dr. Chi Kin Wong.

The research, published in the journal Cell Metabolism holds promise for understanding and treating metabolic diseases.

Known as GLP-1 receptor agonists, for glucagon like peptide 1, these medications mimic the gut hormone GLP1, which regulates blood sugar levels and appetite. Among them are the popular weight loss jabs Ozempic/Wegovy and Mounjaro/Zepbound, but similar compounds have been used for more than 18 years to treat type 2 diabetes.

"One of the really interesting things about the GLP-1 drugs is that beyond the control of blood sugar and body weight they also seem to reduce the complications of chronic metabolic disease.” said Dr. Drucker, who holds the BBDC-Novo Nordisk Chair in Incretin Biology and is Professor of Medicine at the Temerty Faculty of Medicine, University of Toronto.

Research has found that some drugs in these group may lower the risk of heart disease, such as heart failure, stroke, fatty liver disease and kidney disease.

“We know from clinical studies that GLP-1 does all this amazing stuff in people, but we don't fully know how they work”, said Dr. Drucker.

It’s why these drugs are in the limelight.

“For all their promise, GLP-1 agonists have raised more questions than they have answered – a hallmark of a true breakthrough,” wrote Holden Thorp, Science journals’ editor-in-chief, in an Editorial in the latest issue of Science.

Dr. Drucker’s early work on the GLP-1 hormone provided an understanding of how it works at the molecular level and paved the way for multiple diabetes drugs, Ozempic among them. For his work, he has received some of the world’s most prestigious awards in life sciences, most recently the 2023 VinFuture Emerging Innovation Prize and the 2023 Wolf Prize in Medicine. He also received the 2021 Canada Gairdner International Award and the Order of Canada, among others.

Now, Dr. Drucker focused on teasing out how GLP-1 drugs reduce inflammation, which is a common factor in chronic metabolic diseases. Inflammation is the process by which the immune system recognizes and removes foreign agents such as viruses and bacteria and promotes healing. In chronic form, however, it can persist without an external cause and lead to organ damage.

Given that immune cells are embedded within most organs, an obvious assumption was that the drugs dampen inflammation by interacting with GLP-1 receptors on the immune cells. This is the case in the gut, where large numbers of immune cells are activated by GLP-1. But in other organs, the number of immune cells containing GLP-1 receptors is negligible, indicating another mechanism to be at play.