University of Utah researchers are part of an international team, including Danes and Australians, that have developed the world’s smallest, fully functional version of the insulin hormone based on venom from the predatory cone snail. It’s been almost a hundred years since insulin was discovered, but now with this development a potent, fast-acting insulin, based on animal study observations thus far, could accelerate novel insulin treatments that have the potential to dramatically improve the lives of diabetics.
TrialSite News offers a brief of this finding based on a study recently published in Nature Structural and Molecular Biology.
What is important about this development involving University of Utah (“ U of U”)?
According to Danny Hung-Chieh Chou, PhD, U of U Health assistant professor of biochemistry and study corresponding author, “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.” As this advancement could become the basis for a fast-acting insulin Hung-Chieh Chou notes, “That’s an important step forward in our quest to make diabetes treatment safer and more effective.” Note a handful of researchers representing universities in Denmark and Australia took part in this research including the University of Copenhagen, Monash University, Flinders University, La Trobe University, and The Walter and Eliza Hall Institute of Medical Research.
Why are these deadly cone snails important?
Because as reported by Doug Dollemore with University of Utah Health, these sea creatures release plumes of toxic venom containing a unique form of insulin into the water. As fish swim nearby, the insulin infused water actually reduces their glucose levels, thereby temporarily paralyzing them. Immobilized, the snail moves in for the kill, appearing out of its shell to feast. Chou and team earlier found that the cone snail venom was similar to common human insulin. Moreover, the cone snail variety of insulin appears to work faster than fast-acting human insulin now available.
Why would faster-acting insulin be valuable for new therapies?
First, it could lead to a reduce in the risk of hyperglycemia and other serious complications associated with diabetes commented Helena Safavi, PhD, another study co-author and an assistant professor of biomedical sciences at the University of Copenhagen in Denmark. Moreover, the researchers suspect that such a substance if transformed into an FDA-regulated product could advance the performance of insulin pumps or artificial pancreas devices. Professor Safavi commented that the researchers are looking at the current development as the foundation to “help people with diabetes to more tightly and rapidly control their blood sugar.”
What is a key advantage of insulin derived cone snail venom?
This form of insulin lacks a “hinge” component triggering an aggregation or clumping together associated with human insulin as it ultimately is stored in the pancreas, writes Mr. Dollemore. As there is no aggregation or clumping together like that characteristic of human insulin, cone snail insulin is essentially “primed and ready to work on the body’s biochemical machinery” in near real-time.
The Research Hypothesis: Can this natural weapon be converted to a Type I diabetes treatment?
With this knowledge, the team became fixated on how to translate what is essentially a natural weapon of the cone snail into a treatment for people with Type 1 diabetes to accelerate balance and stability in their bodies. Could the actual conversion be done to work in humans? The research would need to overcome some obstacles.
What are some challenges addressed in this preclinical research by the team?
The insulin originating from the cone snail unfortunately is significantly less strong than human insulin. The researchers suspected that a human would need 20 to 30 times more of this type of insulin to actually reduce blood sugar levels.
How did the team overcome these challenges?
The multinational research team employed structural biology and medicinal chemistry methods in an effort to actually isolate four amino acids that support the snail insulin bind to the insulin receptor. Then by effectively truncating a human insulin molecule version less the region associated with clumping, reported University of Utah Health.
Then the researchers took the modified isolated amino acids and integrated them into the human molecule in the quest to design a hybrid that A) doesn’t clump, and B) binds the human insulin receptor with high potency. Essentially creating a hybrid insulin by integrating the modified versions of the amino acids
How did preclinical tests go on laboratory rats?
Very well. In fact, the new hybrid molecule named “mini-insulin” interacted with insulin receptors in ways that the cone snail insulin in fact does not, reported University of Utah. Hence the new interactions actually bound mini-insulin receptors in the rat’s body comparable to human insulin. The researchers had successfully bio-engineered mini-insulin to have the same potency as human insulin, however it acts faster.
The potential value proposition
As Chou quoted, “Mini-insulin has tremendous potential.” He continued, “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 easily synthesize, making it a prime candidate for the development of a new generation of insulin therapeutics.”
This preclinical research, laboratory-based animal research was funded by the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) and the Australian National Health and Medical Research Council.
University of Utah
University of Utah Health provides leading-edge and compassionate medicine for a referral area that encompasses 10% of the U.S., including Idaho, Wyoming, Montana and much of Nevada. A hub for health sciences research and education in the vast Intermountain West region of the United States, “The U” touts a $356 million research enterprise and trains the majority of Utah’s physicians and more than 1,250 health care providers each year at its schools of Medicine, Dentistry and Colleges of Nursing, Pharmacy and Health. With over 20,000 employees, the system includes 12 community clinics and four hospitals. For a decade, U of U has ranked among the top 10 U.S. academic medical centers in the rigorous Vizient Quality and Accountability Study, including top ranking in 2010 and 2016.
Danny Hung-Chieh Chou, PhD, U of U Health assistant professor of biochemistry and study corresponding author
Helena Safavi, PhD, University of Copenhagen and Assistant Professor of Biochemistry, University of Utah
Note, others researchers including those from Australian universities can be viewed at the source.
Call to Action: Although at an early stage, this breakthrough could be of benefit to a biopharmaceutical company interested in new, advanced forms of insulin.