Important properties of insulin have been misunderstood for a century

Disease and treatment 21. mar 2023 2 min Professor and Group Leader Nikos S. Hatzakis, Professor Knud Jørgen Jensen Written by Kristian Sjøgren

A new discovery about insulin may contribute to solving one of the greatest challenges for people with type 1 diabetes: despite using insulin, their blood glucose fluctuates greatly.

Insulin helps to regulate the blood glucose of people with type 1 diabetes, but blood glucose can still fluctuate and lead to both dangerously high and low levels.

New research has shown that insulin in solution acts very differently than researchers have thought in the century since insulin was discovered.

This revelation opens the door to developing optimal insulin formulations that may keep blood glucose more stable for people with type 1 diabetes.

“We thought that insulin acts in a certain way, but we found that insulin in solution acts quite differently. Fewer insulin molecules exist as monomers, which act rapidly, and far more exist in clusters, which act slowly. Although we studied insulin in solution, this may have implications for how insulin affects blood glucose in both the short and long term,” explains a lead author behind the study, Knud Jørgen Jensen, Professor, Department of Chemistry, University of Copenhagen.

The research has been published in Communications Biology.

Several forms of insulin

Researchers have long known that insulin is not simply insulin. It was assumed that insulin can exist in three forms.

The individual molecules, the monomers, are the active form of insulin and contribute to absorbing glucose from the blood.

The monomers can join in pairs as dimers, which can join in a tri-molecular reaction to form hexamers, the form in which the body stores insulin when not required.

When people with type 1 diabetes take insulin, the proportions of monomers and hexamers affect how rapidly the insulin works and for how long.

However, the new research shows that the ratio between the monomers, dimers and hexamers in insulin in solution differs from what researchers previously thought.

Microscopic examination of insulin

The researchers used total internal reflection fluorescence microscopy to examine the individual insulin molecules in detail.

They examined human insulin in solution, which enabled them to follow each individual molecule as it forms the clusters of molecules.

The study shows that the proportions of monomers and hexamers in human insulin differ greatly from what was assumed from earlier studies in solution: only half as many monomers and many more hexamers in solution.

“These experiments were carried out using our very advanced microscope and not on a living animal, and we should be careful in transferring the results to humans. But we suspect that this finding is related to how insulin works. This does not mean that the current formulations are dangerous for people with type 1 diabetes, but it opens up the possibility of developing optimal insulin formulations that are much closer to the effectiveness needed,” says Nikos Hatzakis, Professor, Department of Chemistry, University of Copenhagen, who led the study.

Hundreds of individual insulin processes

The studies of insulin also show that the insulin molecules do not bind in clusters in the way researchers previously had thought.

Instead of monomers binding together into dimers that then transition into hexamers, insulin can exist as monomers, dimers, trimers, tetramers, pentamers and hexamers. When insulin forms hexamers, a dimer and a tetramer join together.

“This is the first time we have this much more detailed understanding of how insulin species assemble and form clusters. Our microscopy results revealed how rapidly the process occurs and the relationships between the clusters,” explains Nikos Hatzakis.

Potential to develop better insulin formulations

With the new understanding, drug developers can revisit old insulin formulations to determine whether they actually act in solution as intended.

Perhaps the ratio between the rapid monomers and the slow hexamers differed from what was assumed and the insulin worked differently than originally intended.

Improved understanding of insulin may also enable drug developers to design optimal insulin formulations that keep blood glucose more stable rather than just lowering it.

“The cluster formation of insulin strongly influences how insulin works. One difference between the rapid and slow insulin formulations is how rapidly the molecules break apart or gather in clusters. With modern equipment, we can easily determine the actual concentrations of the clusters and hopefully use that to develop insulin with exactly the desired profile of effectiveness,” concludes Knud Jørgen Jensen.

Enhanced hexamerization of insulin via assembly pathway rerouting revealed by single particle studies” has been published in Communications Biology. Co-author Knud J. Jensen and Nikos S. Hatzakis received funding for the project through a grant from the Novo Nordisk Foundation to the Center for Biopharmaceuticals and Biobarriers in Drug Delivery. In addition received funding from the VILLUM FONDEN. Several researchers from the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen participated in the study.

Nikos Hatzakis' main research interest is to obtain a fundamental understanding of the parameters underlying regulation of protein function and how ab...

His research is at the interface between synthetic chemistry, biology, and biophysics; it includes peptide and carbohydrate chemical biology and nanos...

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