A large portion of a diabetic’s insulin dose is unlikely to work as expected, according to new research.
The discovery provides a tool to develop better insulin formulations that millions of people around the world depend on.
If you are one of the many millions of type 1 diabetics worldwide, you know that there is a difference in how quickly and how long insulin preparations work in the body. For diabetics, these differences are crucial for effective treatment. Taking too little or too much insulin can lead to very low or high blood sugar. Both situations can be dangerous.
“There are only half as many individual molecules in insulin as we thought.”
Absorption of insulin in the body is controlled by how the insulin molecules cluster together. While a single molecule provides rapid action in the body, groups of six molecules – known as hexamers – are long-acting. For decades, it has been assumed that insulin assembles with a certain distribution of molecular clusters of either one, two or six molecules. Pharmaceutical products are designed based on this assumption.
But with the help of highly advanced single-molecule microscopy, a team of researchers is the first to prove that this important point has been wrong for years.
“It is now obvious to us that we have got things 200% wrong. There are only half as many individual molecules in insulin as we thought. Instead, there are many more six-molecule clusters than we assumed. These experiments were not done on animals, but were done under a microscope, and one should be careful how to interpret their direct application to humans,” says Professor Nikos Hatzakis of the University of Copenhagen’s chemistry department.
“However, our results may mean that when we think we are delivering a certain dose, it may mean that insulin is behaving in a different way than expected and that even better insulin therapeutics can be developed.”
In other words, much of the insulin that diabetics currently put into their bodies may not be absorbed as expected. While the researchers emphasize that this is not entirely dangerous for patients, it shows that there is great potential for the development of more accurate drugs.
The study appears in the journal Communication Biology.
Increase in insulin
“Insulin preparations are getting better and better over the years and many diabetics are well regulated. However, the development of insulin preparations has been based on a certain assumption about how the molecules are assembled. With the crude standard model, this process was never assessed at a detailed level. That’s what we can do,” says the study’s other lead author, Professor Knud J. Jensen of the chemistry department.
“This does not mean that current insulin drugs are bad or that patients have been given the wrong drugs. But we now have a basic understanding of how insulin behaves and how much might be available in the body as a fast-acting drug. Now we have the right method to provide us with accurate data. We hope the industry will use this or a similar tool—both to review current insulin formulations and to develop new ones,” Hatzakis adds.
The research results were achieved through a mixture of chemistry, machine learning, simulations and advanced microscopy. The researchers began by directly observing the process by which each insulin molecule joins forces with other molecules to assemble into clusters. This allowed them to see how quickly each cluster formed. The researchers examined about 50,000 clusters.
Knowing the exact distribution of the different groups in a given amount of insulin is fundamental when developing drugs that must have either short- or long-acting effects on the body:
“Insulin grouping is incredibly important to how the formulations work. Because the difference between a fast- and slow-acting insulin preparation depends on how quickly the molecules assemble into groups and how quickly they disassemble. Access to highly advanced equipment makes it relatively simple and fast to gain knowledge of the exact concentrations, knowledge that is also quite sophisticated at the same time,” says lead author Freja Bohr, a Ph.D. in Hatzaki’s research group.
In addition to the different distribution of molecular clusters, the observations also show that cluster formation is a much more complex process than once assumed. Clusters can both grow and shrink at many more different intervals than previously assumed.
“Without being able to say exactly how much, this will allow the number of ways in which preparations are designed to be expanded. This could lead to an insulin with a different action profile that reduces blood sugar fluctuations in patients – which remains a major challenge,” says Bohr.
Jensen believes the new knowledge will be able to optimize all types of new insulin and make a difference for the more than 40 million children and adults who take insulin on a daily basis. Life as a diabetic is still not without problems:
“Sometimes I get questions from parents asking if there is anything better to treat their young children. When a person has poorly controlled type 1 diabetes, they can feel awful for long periods of time. Among other things, they may wake up with nightmares, feel sick due to low or high blood sugar concentrations, be at risk of passing out from low blood sugar, and suffer subsequent damage to their eyes and feet later in life. So if life can be made better for children by making better insulin, that’s fantastic!” Jensen says.
Source: University of Copenhagen