An international team of researchers have developed the smallest, fully functional version of insulin, combining human insulin with the fast-acting potential of a venom insulin produced by predatory cone snails.
Cone snails, found slithering across coral reefs, are constantly on the prowl for prey. Some, such as Conus geographus, release plumes of toxic venom that contain a unique form of insulin into the surrounding water. This causes fish blood glucose levels to plummet, temporarily paralysing them so the snail can take its prey.
In earlier studies, the researchers discovered that this venomous insulin had many biochemical traits in common with human insulin – and it appears to work faster than the quickest-acting human insulin currently available.
Faster-acting insulin would diminish the risk of hyperglycaemia and other serious complications of diabetes, says Helena Safavi, Ph.D., a study co-author and an assistant professor of biomedical sciences at the University of Copenhagen in Denmark. It also could improve the performance of insulin pumps or artificial pancreas devices, which automatically release insulin into the body as needed.
The researchers found that insulin derived from cone snail venom lacks a ‘hinge’ component that causes human insulin to aggregate or clump together so it can be stored in the pancreas. These aggregates must break up into individual molecules before they can begin to work on blood sugar, a process that can take up to an hour. Since cone snail insulin doesn’t aggregate, it is, in essence, primed and ready to work on the body’s biochemical machinery almost immediately.
Intrigued, the researchers began to investigate ways to transform the insulin that cone snails use as a weapon into a different form: one that people who have Type-1 diabetes could use to rapidly restore equilibrium in their bodies.
“We had the idea of making human insulin more snail-like,” says Safavi, “so, we sought to basically take some of the advantageous properties from the snail and graft them onto the human compound.”
The researchers thought this was possible because cone snail insulin essentially has the same basic structure or ‘backbone’ as human insulin. However, the snail’s insulin is far less potent than human insulin, and the researchers suspect that humans would require 20 to 30 times more of the cone snail insulin to lower their blood sugar levels.
In this new study, Dr Danny Hung-Chieh Chou, Ph.D, one of the study’s corresponding authors, sought to overcome these problems. First, they used structural biology and medicinal chemistry techniques to isolate four amino acids that help the snail insulin bind to the insulin receptor. Then, they created a truncated version of a human insulin molecule without the region responsible for clumping.
The team integrated modified versions of these amino acids into the human molecule in hopes of creating a hybrid that does not clump and binds the human insulin receptor with high potency.
In tests with laboratory rats, this hybrid insulin molecule, which the scientists call “mini-insulin,” interacted with insulin receptors in ways that cone snail insulin doesn’t. These new interactions bound mini-insulin to insulin receptors in the rat’s body just as strongly as normal human insulin would. As a result, mini-insulin had the same potency as human insulin but acted faster.
“Mini-insulin has tremendous potential,” Chou says. “With just a few strategic substitutions, we have generated a potent, fast-acting molecular structure that is the smallest, fully active insulin to date. Because it is so small, it should be easy to synthesise, making it a prime candidate for the development of a new generation of insulin therapeutics.”
“We now have the capability to create a hybrid version of insulin that works in humans, and that also appears to have many of the positive attributes of cone snail insulin,” says Chou. “That’s an important step forward in our quest to make diabetes treatment safer and more effective.”
The study appears in Nature Structural and Molecular Biology.