Fast-acting hybrid insulin borrows tricks from sea snail venom
Insulin has proven an invaluable, life-saving hormone since the first diabetes sufferers were injected with it in the 1920s, but that doesn’t mean there isn’t room for improvement. Scientists at the University of Utah have been coming at this from an interesting, nature-inspired angle, borrowing useful elements of cone snail venom to produce a potent hybrid “mini-insulin” that acts far more swiftly, and could make treating diabetes far more effective as a result.
The reason the University of Utah researchers were lured toward the humble cone snail as part of their research is due to the creature’s cunning approach to trapping its prey. When a potential dinner is sighted, the mollusks are able to release plumes of venomous cocktails that paralyze fish by causing sharp drops in their blood-sugar levels.
This is due to a form of fast-acting insulin contained within the cocktail, which induces a type of hypoglycemic sedation in the fish. The reason it acts almost instantly is because the cone snail venom is missing the components of human insulin that causes individual molecules to clump together. This means injected insulin has to break apart before it can perform its role of keeping blood sugar levels in check in sufferers of diabetes.
Conversely, the cone snail venom comes primed and ready to act. The same research team found through laboratory experiments in 2016 that this cone snail insulin was capable of latching onto human insulin receptors, raising the prospect of a faster-acting form of insulin for treating diabetes. But some key hurdles remained.
The researchers ran into trouble as they tried to adapt the cone snail venom for use in humans, finding that it was nowhere near as potent as the traditional form of the hormone. The team guessed that a dose would need to be 20 to 30 times stronger to effectively lower blood sugar levels in a human patient.
Now the team is reporting another significant breakthrough that appears to overcome this. Through their continued experiments using structural biology and chemistry techniques to study the makeup of the cone snail insulin, the scientists isolated four amino acids that help it bind to the insulin receptor. They then engineered a version of human insulin without the components that cause clumping and with these newly unearthed amino acids included.
The result was what the scientists describe as the world’s smallest fully functional version of a hormone, which they’ve dubbed “mini-insulin.” Laboratory tests on rats found that this hybrid insulin bound to the insulin receptors just as strongly as human insulin does, offering the same level of potency and with a much faster-acting nature.
"Mini-insulin has tremendous potential," says the University of Utah’s Danny Hung-Chieh Chou, study author. "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 synthesize, making it a prime candidate for the development of a new generation of insulin therapeutics."
If the team’s fast-acting hybrid insulin can adapted for use in humans, which will involve a great deal more investigation, it could make managing blood-sugar levels more efficient, while also lessening the risk of complications like hyperglycemia.
"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 research was published in the journal Nature Structural and Molecular Biology.
Source: University of Utah via Phys.org