Monash University researchers have discovered how a hormone peptide called glucagon could better treat conditions such as obesity and type 2 diabetes, which affect billions of people.
Glucagon – like insulin, from the pancreas – has been known about for 100 years but the way it works is only beginning to be understood. An international team led by the Monash Biomedicine Discovery Institute has found potential new ways to make better medicines using pre-clinical models and cell experiments combined with viral/molecular technologies.
The groundbreaking findings are now published in Nature Communications, revealing how glucagon sends signals within cells and the liver and, for the first time, defines how tiny membranes within the cells shift proteins around – the vesicle trafficking protein SEC22B.
Lead author, Associate Professor Adam Rose, the head of Monash's Nutrient Metabolism and Signalling Lab at the Biomedicine Discovery Institute said: "by creating a clearer understanding of how glucagon works, we can potentially create more refined and better therapies for diseases such as obesity and type 2 diabetes. This can have positive ripple down effects economically as well as societally, but more importantly to improve the lives of people with metabolic disease."
Associate Professor Rose said despite glucagon being discovered more than 100 years ago, how it signals in the liver was still largely unknown. Glucagon is secreted by certain cells in the pancreas to increase glucose levels in the blood and liver, making it part of the type 2 diabetes puzzle, keeping blood glucose up, while insulin keeps it down. The two work together to stabilise blood glucose but glucagon also affects many other aspects of metabolism.
"Glucagon is a relatively long-known hormone, but we still didn't know how glucagon signals within the liver to induce its many effects," said Associate Professor Rose. "Our findings change this by uncovering a multitude of new possibilities."
He said glucagon-based medicines were emerging as the best of their kind to treat obesity, type 2 diabetes and fatty liver disease. "Our studies open up avenues to discover how these therapies actually work.
We examined one such possibility, and for the first time showed that a vesicle trafficking protein is involved in nearly all of glucagon's metabolic actions."
The study received seed funding from the Endocrine Society of Australia and a Project Grant from Diabetes Australia and involved collaborators from the University of New South Wales with international researchers from Germany and the United States.
Associate Professor Rose said the next step toward better type 2 and obesity medicines was about better understanding the vesicle trafficking protein SEC22B and how it works within a liver cell to affect glucagon action.
Read the full paper in Nature Communications: Phosphoproteomics-directed manipulation reveals SEC22B as a hepatocellular signaling node governing metabolic actions of glucagon. DOI:10.1038/s41467-024-52703-w
