Helena Safavi, left, helps her colleague, José Rosado from Maputo, Mozambique, sort cone snails collected by scuba divers near the Solomon Islands in the south Pacific. The scientists set up a mobile lab on the diving ship to dissect and preserve the biological samples. [Adam Blundell]

Nearly a century after insulin was discovered, an international research team, headed by scientists at the University of Utah Health (U of U Health) has developed what is claimed to be the smallest, fully functional version of the hormone. The insulin analog is based on a fast-acting venom insulin produced by fish-hunting predatory cone snails, but also displays the full potency of human insulin and binds to the human insulin receptor (hIR). Tests in rodents suggested that the mini-insulin, or “Mini-Ins,” demonstrated similar bioactivity to human insulin. The researchers claim the Mini-Ins could represent a springboard for developing fast-acting insulins that improve the lives of people with diabetes.

“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,” said Danny Hung-Chieh Chou, PhD, a U of U Health assistant professor of biochemistry and one of the study’s corresponding authors. “That’s an important step forward in our quest to make diabetes treatment safer and more effective.”

Chou and colleagues reported on the development and structure of the Mini-Ins in Nature Structural and Molecular Biology, in a paper titled, “A structurally minimized yet fully active insulin based on cone-snail venom insulin principles.”

After disabling a fish with its potent venom, a cone snail devours it. Insulin extracted from cone snail venom could be used to develop a new, fast-acting insulin for human use. [University of Utah Health]

When out hunting on coral reefs, the predatory cone snail, Conus geographus, releases into the surrounding water a toxic venom that contains a unique form of insulin. The fast-acting insulin causes fish blood glucose levels to plummet rapidly, resulting in temporary paralysis, and giving the snail time to emerge from its shell and swallow the subdued victim whole.

In earlier research, Chou and colleagues discovered that this venom insulin had many biochemical traits in common with human insulin. It also appeared to work faster than the swiftest-acting human insulin currently available. “Our recent discovery of specialized venom insulins in the fish-hunting cone-snail provides a unique opportunity to investigate the pharmacological potential of these fast-acting natural proteins that evolved to affect prey glucose homeostasis,” the investigators wrote.

A faster-acting insulin available for human diabetes patients would lessen the risk of hyperglycemia and other serious complications of the disorder, suggested co-author Helena Safavi, PhD, an assistant professor of biomedical sciences at the University of Copenhagen. It also could improve the performance of insulin pumps or artificial pancreas devices, which automatically release insulin into the body as needed. “We want to help people with diabetes to more tightly and rapidly control their blood sugar,” she noted.

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 is monomeric and doesn’t aggregate, it’s effectively primed and ready to work almost immediately.

Intrigued, the researchers began to investigate ways to transform the cone snail venom insulin, Con-Ins-G1, into a form that could be used by individuals with type 1 diabetes, to rapidly restore glucose levels in their bodies. “As monomeric formulation of insulin leads to faster absorption on subcutaneous injection into patients, a key question is whether the structural features that enable Con-Ins–G1’s activity against hIR can be transferred to a monomeric human insulin backbone to produce fast-acting, therapeutic insulin analogs,” the team commented.

“We had the idea of making human insulin more snail-like,” added Safavi, who is also an adjunct professor of biochemistry at U of U Health. “So, we sought to basically take some of the advantageous properties from the snail and graft them onto the human compound.” This was conceptually feasible because cone snail insulin essentially has the basic structural backbone as human insulin. However, one drawback was that the native snail insulin is far less potent than human insulin. The researchers suspected that humans would require 20 to 30 times more of the cone snail insulin to lower their blood sugar levels.

For their newly reported study, Chou and colleagues worked to overcome this problem. First, they harnessed 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 that is responsible for clumping. The team integrated modified versions of these amino acids into the human molecule in the hope of creating a hybrid that does not clump and binds the human insulin receptor with high potency.

In tests with laboratory rats, the resulting hybrid mini-insulin molecule interacted with insulin receptors in ways that cone snail insulin doesn’t. “Our results indicate that an alternative binding mode to the insulin receptor (characterized by weaker primary binding-site interaction and stronger secondary binding-site interaction, is achieved by Mini-Ins …” the scientists wrote. These new interactions bound mini-insulin to insulin receptors in the rat’s body just as strongly as would normal human insulin. As a result, the mini-insulin exhibited the same potency as human insulin, but acted faster. And there was no evidence that the molecule would trigger an immune system reaction. “Mini-Ins also did not generate an antibody response, indicating that the four mutations do not change its immunogenicity in mice from that of human insulin,” the team commented. “Given its monomeric properties, Mini-Ins represents a new platform for therapeutic development of prandial insulins.”

“Mini-insulin has tremendous potential,” Chou stated. “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.”

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