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January 10, 2013

Insulin Docking Images Could Improve Diabetes Treatments



Insulin Docking
 Medical Research
Scientists have long been unsure how insulin binds to the insulin receptor on the surface of cells to allow them to take up sugar from the blood. Now, a clear answer has now been found with a team of scientists capturing the first three-dimensional images of insulin “docking” to its receptor. The new knowledge may be used to develop new and improved insulin medications to treat type 1 and type 2 diabetes.
For more than 20 years, researchers have been trying to establish how insulin binds to an insulin receptor.  Now a breakthrough discovery about how this occurs could help in the development of improved types of insulin for treating both type 1 and type 2 diabetes.

The research was conducted by the Walter and Eliza Hall Institute and used the Australian Synchrotron in Melbourne. The study was published in the journal Nature.

Led by Associate Professor Mike LawrenceDr Colin Ward and Dr John Menting, the research team now have a clear understanding of the insulin binding mechanism.

For the first time, scientists have captured, in detail, the way in which insulin uses the insulin receptor to bind to the surface of cells. This binding is necessary for the cells to absorb sugar from the blood for their energy.

Associate Professor Lawrence from the institute’s Structural Biology division said the team was excited to reveal for the first time a three-dimensional view of insulin bound to its receptor. “Understanding how insulin interacts with the insulin receptor is fundamental to the development of novel insulins for the treatment of diabetes,”

Lawrence said. “Until now we have not been able to see how these molecules interact with cells. We can now exploit this knowledge to design new insulin medications with improved properties, which is very exciting.”
The Australian Synchrotron’s MX2 microcrystallography beamline was critical to the project's success. "If we did not have this fantastic facility in Australia and their staff available to help us, we would simply not have been able to complete this project,” Lawrence said.

“We have now found that the insulin hormone engages its receptor in a very unusual way,” Lawrence said. “Both insulin and its receptor undergo rearrangement as they interact – a piece of insulin folds out and key pieces within the receptor move to engage the insulin hormone. You might call it a 'molecular handshake'.”

Australia, along with the rest of the world, is facing an increasing epidemic of type 2 diabetes. There are now approximately one million Australians living with diabetes and around 100,000 new diagnoses each year.

Insulin Docking at the insulin receptor
Lawrence demonstrates where insulin binds to the insulin receptor

“Insulin controls when and how glucose is used in the human body,” Lawrence said. “The insulin receptor is a large protein on the surface of cells to which the hormone insulin binds. The generation of new types of insulin have been limited by our inability to see how insulin docks into its receptor in the body.

“Insulin is a key treatment for diabetics, but there are many ways that its properties could potentially be improved,” Lawrence described. “This discovery could conceivably lead to new types of insulin that could be given in ways other than injection, or an insulin that has improved properties or longer activity so that it doesn't need to be taken as often. It may also have ramifications for diabetes treatment in developing nations, by creating insulin that is more stable and less likely to degrade when not kept cold, an angle being pursued by our collaborators. Our findings are a new platform for developing these kinds of medications.”



SOURCE  Walter and Eliza Hall Institiute

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