In a recent study, researchers from the Walter and Eliza Hall Institute have made a discovery that could make therapeutic insulins more effective by better mimicking the way insulin works in the body.
The findings could improve treatments for diabetes, a disease that impacts the lives of millions of people worldwide.
The study reveals the first definitive 3-D image of how insulin successfully interacts with its receptor in a process that is crucial for instructing cells to lower blood sugar levels in the body.
The receptor is a ‘gatekeeper’ for transmitting information into cells.
Understanding exactly what this process looks like could inform the design of faster-acting and longer-lasting insulin therapies.
Lead author Associate Professor Lawrence said he was thrilled to have resolved how insulin triggers cells to lower blood sugar levels.
It is well established that insulin instructs cells to lower blood sugar levels in the body by binding to a receptor that is located on the cell surface.
But the problem was that no one knew precisely what was occurring during the interaction.
Current insulin therapies are sub-optimal because they have been designed without this missing piece of the puzzle.
In the study, together with their collaborators in Germany, the researchers have produced the first definitive 3-D image of the way in which insulin binds to the surface of cells in order to successfully transmit the vital instructions needed for taking up sugar from the blood.
The team said the detailed image was the outcome of a collaboration between structural and cell biology experts from the Institute.
The worked together with both cryo-electron microscopy specialists at EMBL in Heidelberg and an insulin receptor specialist from the University of Chicago.
They knew that insulin underwent a physical change that signaled its successful connection with its receptor on the cell surface.
But they had never before seen the detailed changes that occurred in the receptor itself, confirming that insulin had successfully delivered the message for the cell to take up sugar from the blood.
The team at the Institute carefully engineered individual samples of insulin bound to receptors, so that their collaborators could use cryo-electron microscopy to capture hundreds of thousands of high-resolution ‘snap shots’ of these samples.
They then combined more than 700,000 of these 2-D images into a high-resolution 3-D image showing precisely what the successful binding between insulin and its receptor looks like.
It was at that point they knew we had the information needed to develop improved insulin therapies that could ensure cells would respond correctly and carry out the functions necessary to lower blood sugar levels.
The findings meant it would now be possible to design insulin therapies that could mimic more closely the body’s own insulin.
In the near future, pharmaceutical companies will be able to use our data as a ‘blueprint’ for designing therapies that optimize the body’s uptake of insulin.
There has already been great interest in these results and their application, and the Institute has a network of collaborations underway.
The work was funded in part by the Australian National Health and Medical Research Council.
The study is published in Nature Communications.
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Source: Nature Communications.
