For decades, it has been believed that only one pathway manages how sugar is stored and used in the human body. However, breakthrough research has now discovered a previously unknown hidden switch that can directly regulate stored sugar, or glycogen, inside cells.
The findings could revolutionise how diabetes, heart disease, liver disease, and a set of rare disorders that currently have no treatmentoptions.Researchers at the Walter and Eliza Hall Institute discovered a never-before-seen mechanism our bodies use to regulate sugar, which rewrites the fundamental rules of biology and opens a new frontier in science. The study findings are published in Nature.
New mechanism in which the body controls stored sugar
When we eat foods containing sugar, our bodies convert the excess into glycogen, which is mainly stored in the liver and muscles.
Scientists have studied glycogen metabolism for centuries. This well-defined pathway is taught to every biology and medical student across generations.Professor David Komander, co-lead author on the study, and his team added a new chapter to what was previously believed to be complete.“It’s quite likely biology books will need to be amended as a result of our findings. We’ve uncovered a second pathway where glycogen can be directly regulated – likely on demand.
This is an exciting breakthrough for people living with diseases caused by excessive glycogen,” Prof Komander, also head of WEHI’s Ubiquitin Signalling Division, said, in a release.This is the first study to explore a potential therapeutic process that could directly reduce the amount of sugar stored in the body.
A potential treatment for GSD?
Glycogen Storage Diseases (GSD) are a group of rare inherited disorders which occur when the body can’t properly make or break down glycogen.
There are often no treatment options for this. But excessive glycogen is a troublemaker. It is linked to conditions like diabetes, obesity, liver and heart disease. These diseases are triggered by glycogen accumulation. There are no therapies that can directly attack the glycogen molecule, yet.
But the new discovery changes this.“Exciting new drugs – such as Ozempic – are transforming how we manage blood sugar, indirectly via hormonal regulation.
Without being able to regulate glycogen itself, it is hard to combat its accumulation – the root cause of many diseases. That’s why our study is exciting. We’ve found a way to go straight to the source,” Prof Komander added.
Ubiquitin, the hidden hero
Ubiquitin is a protein that attaches to other proteins, helping the body spot and remove damaged ones. Glycogen, on the other hand, is a sugar, not a protein. But the new study found that ubiquitin can also attach to sugars in animal models and human cells!Ubiquitin is finally getting its due credit, according to co-lead author Dr Simon Cobbold.
“Ubiquitin is really an unsung hero that has been quietly working in the background all this time, keeping us alive.” This breakthrough was possible thanks to NoPro-clipping, a cutting-edge technique developed by Dr Cobbold, Prof Komander, and first author, Marco Jochem, over the past four years.This pioneering technique helped the researchers study ubiquitin in detail. “Without our tools and method, this remarkable process would have remained invisible.
That’s the beauty of NoPro-clipping – it’s allowing us to study a canvas of molecules the ubiquitin field has overlooked all this time,” Dr Cobbold said.“Not only can we use it to detect ubiquitinated glycogen – we can also uncover ubiquitinated metabolites like glycerol and spermine, which we’ve discovered for the first time in all our cells. Our discovery is rewriting the fundamental rules of biology and ubiquitin signalling.
And I’m sure we’ve only hit the tip of the iceberg,” PhD student Marco Jochem explained the versatility of the tool.
What did they find?
Using NoPro-clipping, the researchers were able to visualise how ubiquitin attached to glycogen inside the livers of mice when they were fed and fasted. They found that when the mice were in a fasted state, their glycogen levels depleted as they needed energy. Ubiquitin ‘tags’ increased during glycogen depletion. The findings outline a new pathway of glycogen metabolism. Changes in ubiquitin tags on sugar show they help control when glycogen is released.
The researchers also found that increasing these tags reduced the amount of glycogen in cells. If these breakthroughs can be applied in animals and humans, it could open new ways to tackle diseases.
