Since its discovery, insulin has been the subject of numerous scientific breakthroughs. Richard Elliott looks at what is special about the molecule and talks to three researchers studying its role in diabetes
Insulin, a hormone secreted by the pancreas, is at the heart of all forms of diabetes. Type 1 occurs when the body produces little or no insulin, whereas Type 2 is caused by impaired insulin production and resistance to the insulin that is produced.
As a result, people with Type 1 and more than 40 per cent of people with Type 2 require insulin injections to manage their condition. As insulin plays such an important role in the development and treatment of diabetes, scientists all over the world have strived for many years to learn all they can about it.
Since its discovery in 1921 and its first use to treat diabetes in 1922, major scientific breakthroughs have helped determine the exact three dimensional structure of insulin and the key sites at which it takes effect. Moreover, technological advances have enabled production of human insulin, and the creation of devices to improve safety and comfort when injecting it into the body.
You could even say that insulin is intimately connected with research into human biology. It was the first protein ever to be sequenced (by British biochemist Frederick Sanger in 1955), and the first protein ever to be artificially produced in the laboratory (by US and German scientists in the early 1960s).
However, despite all we have learned about insulin in the past 90 years, there is much we still do not know about the role of this molecule in diabetes. Three Diabetes UK funded researchers provide their insights on the progress being made.
Looking back – and forward
Professor Ken Siddle at the University of Cambridge has been working as a biochemist for more than 40 years and has seen how scientific research has slowly advanced our understanding of insulin.
“When I began my career, we knew almost nothing about how insulin worked,” he says. “We knew that it stimulated glucose uptake into cells but really had no idea how it did it. In the last 40 years we’ve learned that there are insulin receptor proteins on the surface of cells, we’ve learned what sort of proteins these receptors are and what sort of signals they produce inside the cell.
We also understand the structure of insulin itself in incredible atomic detail. But there are still lots of unanswered questions about how insulin is made in the beta cells of the pancreas and how it acts on muscle, liver and fat.”
Naturally occurring variation in the genetic code within the body’s cells contributes to a wealth of human diversity (such as differences in eye colour) but also contributes to the risk of health conditions like diabetes.
With help from Diabetes UK, Prof Siddle has been exploring the ways in which this variation can influence the action of insulin and similar proteins known as ‘insulin like growth factors’ that are involved in cell signalling. He has also studied the insulin receptor on the cell surface and the way that it binds insulin and activates the signalling pathways that control glucose uptake and other aspects of cell signalling.
Though research like this is concerned with only one small part of a large and complex field, Prof Siddle hopes that his work will help improve our understanding of the pathways that determine insulin sensitivity and resistance.
“We want to understand the basic biochemical and molecular pathways that underpin insulin action,” he says. “If we can do that, then we will have a framework for understanding how such pathways malfunction in diabetes. In the future, such pathways could be targeted by novel treatments or provide early indications of diabetes to allow people to modify their lifestyles in ways that would help prevent the onset of the condition.”
Overall, Prof Siddle is optimistic about the future. Within the next 10–20 years he thinks that there will be both better definitions of the different causes of diabetes and a wider range of drugs available for targeting those causes. “That involves a very long process,” he says, “because there just aren’t enough hours in the day and scientists in the world to follow up every interesting lead. It’s a matter of using scarce resources effectively and getting the right people to filter out the right bits of information – that’s the art of good science.”
Although we know a lot about the structure and function of insulin itself, there is one insulin-related molecule that scientists are keen to learn more about. When insulin is first produced in the pancreas, it is initially known as proinsulin and is bound to another protein molecule known as C-peptide [see diagram, right].
This short molecule helps join the two chains of the developing insulin together and allows them to assemble with the correct shape and structure.
C-peptide is then detached from insulin and both molecules are released into the bloodstream. Until recently, there was little interest in the function of C-peptide and it has been used only as a marker of insulin production, since the pancreas tends to release C-peptide and insulin in roughly equal amounts.
Like insulin, people with Type 1 diabetes produce little or no C-peptide, while those with Type 2 may be resistant to its actions. Therefore, when people are newly diagnosed with diabetes, doctors often give them a C-peptide test to work out how much insulin they are producing and help determine whether they have Type 1 or Type 2. Recent scientific evidence suggests that C-peptide can help prevent diabetes-related complications, such as nerve and kidney damage, but the details of how this occurs are yet to be revealed.
Professor Nigel Brunskill at the University of Leicester describes C-peptide as a ‘partner’ to insulin and suggests that, contrary to past assumptions, it could play an active role and potentially become a useful treatment for diabetes. “It has become clear over the last few years that C-peptide has very important biological functions in the body and seems to affect cells and tissues in a way that would be beneficial in someone who has diabetes,” he explains.
Diabetes UK is funding Prof Brunskill’s research into the cellular proteins that C-peptide binds to and the ways that resistance to it can develop. “Insulin binds to cells through a receptor and alters the way that cells function,” he says. “We believe that C-peptide functions in a similar way, so to unlock its promise we need to understand much more about how it interacts with cells and changes their function.”
Puzzle of glucose uptake
Professor Gwyn Gould’s team at the University of Glasgow focuses on steps that occur after insulin has bound to receptors on the surface of fat and muscle cells. Insulin binding brings about changes within each cell, which cause them to take up glucose from the bloodstream and store it. Prof Gould explains the process in simple terms: “Basically, glucose gets into cells through what you might imagine as a ‘doorway’ within the cell. Insulin increases the number of ‘doorways’ so that each cell can get more glucose inside. It does this by moving these ‘doorways’ from a storage site within the cell up to the cell surface.”
Scientists believe that defects in the movement of these ‘doorway’ proteins could bring about the insulin resistance that causes Type 2 diabetes; but the exact steps by which this occurs and the ways in which these ‘doorway’ proteins do not function properly in diabetes are poorly understood. Diabetes UK funds several studies in Prof Gould’s lab that aim to give a more detailed picture of what is going on. “The ‘doorways’ are packaged in little membrane parcels inside the cell,” he says, “and so what we first seek to understand is the mechanism by which that packaging is achieved. Then we want to understand the mechanism by which the packages move to the cell surface.”
Prof Gould emphasises the complexity of the challenges faced by his team. “Although we have a number of the molecules identified and we have a fair idea of how they might work, it’s a bit like a jigsaw that’s half finished – you can see what the picture is but you can’t really see the absolute detail yet. Without that clear detail, it’s very hard to design an effective therapy or engineer a cure. What we are trying to do, in our very small way, is to put a few more pieces in the jigsaw.”
When he looks back at the last 10 years of progress related to insulin and diabetes, Prof Gould believes that what has been really striking is the ability of researchers to do science, like the Human Genome Project, on a huge scale. “That sort of big biology has really opened up a whole bunch of new questions.
Now it’s important to go back to the small-scale biology: the individual one molecule–one protein at a time approach.” He also suggests that, as our knowledge about the action of insulin in diabetes develops, the scope of research in this area and the range of different experts involved is growing. “The links between different fields are becoming much more extensive and more intertwined than we ever imagined and that I think is really exciting,” he says. “Some of these big links are going to be really hard to address and there is a huge amount to be done, but it’s a fascinating time.”
Moving research forward
In 2011 Diabetes UK aimed to spend £5.8m on research projects related to all aspects of diabetes, including insulin. The charity’s current research portfolio costs about £20m and includes around 125 different grants Dr Iain Frame, Diabetes UK’s Director of Research, emphasises the vital role of the charity in helping research move forward: “It’s important that, when people like Prof Siddell, Prof Brunskill or Prof Gould have a hunch that something might work and an idea for a set of experiments, they can come to us and ask for money to help them prove or disprove their theories.
Through the voluntary contributions that people make to us, we can continue to fund these excellent research projects that will hopefully make a huge difference for people living with diabetes."
Read about Insulin: the facts