For the first time, scientists at Sanofi-Aventis Deutschland GmbH, along with two other research institutions, have uncovered how insulin binds to its cellular receptor and promotes the uptake of glucose from the bloodstream. The findings – published in the journal Nature Communications – have major implications for the development of therapeutic insulins for diabetic patients which are designed to compensate for the lack of functional insulin in regulating blood sugar.
“Current insulin therapies are sub-optimal because they have been designed without this missing piece of the puzzle,” said Associate Professor Mike Lawrence from the Walter and Eliza Hall Institute. “Together with our collaborators in Germany, we have produced the first definitive 3D 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 researchers created a 3D image showing the interaction between insulin and its receptor. In addition to scientists from Sanofi, researchers from the European Molecular Biology Laboratory (EMBL) and the Walter and Eliza Hall Institute also collaborated on the study.
“We knew that insulin underwent a physical change that signalled its successful connection with its receptor on the cell surface,” said Lawrence. “But we 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.”
While the fact that insulin binds to a specific cellular receptor was previously known, it wasn’t known what conformational changes occurred to the receptor to trigger the cell to take up glucose. The new 3D model could lead to the development of both faster-acting and longer-lasting synthetic insulins to treat the millions of people with diabetes around the world.
“My colleagues at the Institute carefully engineered individual samples of insulin bound to receptors so that our collaborators in Heidelberg could use cryo-electron microscopy to capture hundreds of thousands of high-resolution ‘snap shots’ of these samples,” said Lawrence. “We then combined more than 700,000 of these 2D images into a high-resolution 3D image showing precisely what the successful binding between insulin and its receptor looks like. And there it was before our eyes, the full picture in exquisite detail.
It was at that point we 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.”
Since a scientific team from Sanofi helped to make the discovery, it’s likely the diabetes drug developer will be among the first to use their newfound knowledge to develop more effective insulins. Sanofi’s Q2 2018 sales from its global diabetes and cardiovascular business unit totalled over €1.1 billion, and the company is set to release their Q3 earnings next week.
“Going forward, pharmaceutical companies will be able to use our data as a ‘blueprint’ for designing therapies that optimise the body’s uptake of insulin,” said Lawrence. “There has already been great interest in these results and their application, and the Institute has a network of collaborations underway. After more than two decades of research by Melbourne scientists to get to this point, it is phenomenal to have achieved results that will ultimately benefit patients with the development of more effective therapies, particularly for those whose lives are dependent on a daily injection of insulin.”