Professor Eoin McKinney and his team at University of Cambridge have discovered ‘signatures’ of immune cell changes seen only in people who later develop type 1 diabetes. In this Type 1 Diabetes Grand Challenge project, they will search for existing medicines that can rewrite this signature to prevent type 1 diabetes.

Background to the research project

Understanding how type 1 diabetes develops is vital for preventing the condition. Researchers are looking at the biological processes that lead to the immune system dysfunction in type 1 diabetes and ways to block or reverse these.

Mapping signatures of cell changes

One scientist working on this is Professor Eoin McKinney, with funding from the Type 1 Diabetes Grand Challenge. His team has used machine learning to analyse signatures in cell samples from hundreds of people who went on to develop type 1 diabetes. These signatures show patterns of changes in immune cells, which are linked to the development of type 1 diabetes.

There are also similar signatures that show how cells in the body are changed by drugs. There are large data banks of these drug signatures for the many thousands of medicines prescribed for all sorts of conditions. Professor McKinney will use this vast library of drug signatures to search for a way to reverse the changes to the immune system that lead to type 1 diabetes.

What will Professor McKinney do in this project?

The researchers will hunt for matches between the type 1 diabetes signatures they’ve discovered and the drug signatures that have been mapped for individual medicines. When they find a pattern in a drug signature that complements a pattern in their type 1 signature, the medicine has the potential – in theory – to reverse the changes and prevent the condition.

Professor McKinney said: “By collaborating with international groups, we have generated detailed maps of immune cell changes occurring from the earliest stages of T1D through to diagnosis. Now, we plan to use that information to find new treatments that might prevent progression, by matching changes seen before type 1 diabetes to those produced by commonly used medicines. By finding a match, we hope to identify which drugs might be most easily used to reverse or stop disease progression.”

Moving from theory to reality

Professor McKinney will then check if the drugs work in practice by examining how they change immune responses. First in human cells and then in mice, gathering as much information as possible about each drug. This means that when it comes to testing in people, only medicines with the highest chance of success will make the cut.

Rapid progress is possible

The team expects to have a candidate medicine ready to give to people at high risk of type 1 diabetes in a prevention trial much faster than usual. This is because this medicine would have already been through extensive safety testing for its original use. So, if the lab tests are positive, there shouldn’t be anything standing in the way of a clinical trial.

How will this research help people with type 1 diabetes?

The first signs of type 1 immune attack can be detected years before symptoms develop. Finding a medicine that can fend off the condition will give people the chance to protect themselves for longer. And by using an existing medicine – rather than developing a new drug – this breakthrough could come years or decades sooner.

Professor McKinney said: “By selecting candidate treatments rationally based on a match with type 1 data, we will stand the best possible chance of finding a safe and effective approach to stop the condition with real impact for patients everywhere.”

Led by Drs Aida Martinez-Sanchez and  Prashant Srivastava at Imperial College London, along with Dr Teresa Rodriguez-Calvo at Helmholtz Zentrum Munich, this project will investigate how tiny molecules called microRNAs change the function of insulin-making beta cells. Studying how these molecules are different between beta cells from people with and without type 1 diabetes, and in those grown from stem cells, could help to improve the effectiveness of beta cell transplants. 

Background to the research project – every beta cell is unique

In type 1 diabetes, insulin-producing beta cells are destroyed by the immune system. Beta cells are all unique, and some are more prone to the type 1 immune attack. This uniqueness is known as heterogeneity and plays an important role in how type 1 diabetes develops. 

MicroRNAs (miRNAs) are tiny molecules in our cells that switch different genes on and off and change how the cell works. They’re important in beta cell development and function, and differences in beta cell miRNA could be key to why some beta cells are more vulnerable to the type 1 attack. 

Drs Aida Martinez-Sanchez and Prashant Srivastava think that beta cells grown from stem cells – which are being developed as potential treatments for type 1 diabetes –   might have different miRNAs than beta cells found in humans. This could explain why stem cell-beta cells don’t function as well as human beta cells and are often rejected after transplantation if they’re not destroyed by the immune system first. They also suspect that there are differences between beta cell miRNA in people with and without type 1 diabetes. 

What will the team do in this project?

Drs Martinez-Sanchez and Srivastava want to examine differences in the miRNA of different kinds of beta cells. There are two main parts to the research: 

1. In beta cell and pancreas samples from donors with and without type 1 diabetes, they’ll investigate which genes are switched off by miRNAs with a method called AgoTRIBE. This works by ‘tagging’ switched off genes in individual beta cells. They’ll also use an advanced microscope to look for the tags, helping them to find out more about miRNA and how it impacts beta cell function. 
2.  Next, they’ll use AgoTRIBE to understand whether miRNA in beta cells grown from stem cells is different to that in beta cells from donors. They’ll also use a technique that will help them understand more about the role of miRNAs in beta cell survival and healthy functioning. 

How will this research help people with type 1 diabetes?

Understanding how miRNAs influence the behaviour and survival of beta cells could help scientists to develop healthier, longer-lasting lab grown beta cells. This could help to improve the effectiveness of beta cell transplants by making sure the transplanted cells are tougher and less likely to be rejected, which in turn would reduce the need for insulin injections.  

This research could also shed more light on how to protect beta cells from the immune attack, potentially preventing or slowing down the progression of type 1 diabetes.  

Dr Aida Martinez-Sanchez said:

“MicroRNAs are tiny molecules essential for keeping insulin-producing beta cells alive and well. However, not all beta cells are the same—some are more resistant to immune attack, while others are more vulnerable. Also, some beta cells are better at releasing insulin than others. In this project, we will use pioneering molecular and cellular biology techniques to explore whether microRNAs contribute to these differences.

“Identifying which miRNAs to manipulate could help us to grow the very best beta cells in the lab. The complex methodologies we’re developing have the potential to form the basis of future research in other important aspects of beta cell biology, such as how to reduce the risk of transplant rejection, or delay or prevent beta cell destruction in type 1 diabetes.”

Led by Professors Shoumo Bhattacharya and David Hodson at the University of Oxford, this project will take inspiration from tick saliva to develop a defence mechanism for beta cells transplanted into people with type 1 diabetes. This research could reduce the need for immunosuppressing drugs, leading to longer-lasting and more successful beta cell transplants.  

Background to the research project – taking evasin action

Some people with type 1 diabetes can have insulin-producing beta cells (taken from donors or grown from stem cells) transplanted into them, which replace their own cells that have been destroyed by their immune system. But the immune system often tries to destroy these as well. This means that transplant recipients need to take strong drugs that dial down their immune system, called immunosuppressants.  

And even with immunosuppressants, the immune system still eventually kills off the transplanted cells and most people end up needing insulin again after a few years. 

Transplanted beta cells release chemical signals called chemokines, which act like beacons that lead the immune system to attack them in type 1 diabetes. Researchers have struggled to find ways to block these signals, because there are so many different types of chemokines. 

Parasitic ticks have evolved proteins called evasins which can block a wide range of chemokines, allowing them to bite through skin and feed on blood without being detected by the immune system. Professors Shoumo Bhattacharya and David Hodson think evasins could unlock new ways to block chemokines released by transplanted beta cells, helping them to evade the type 1 immune attack and survive and thrive for longer after transplantation, without immunosuppressants. 

What will the team do in this project?

Professors Shoumo Bhattacharya and David Hodson have already identified the part of the tick evasin that’s responsible for blocking chemokines, called a peptide. In this project, they plan to make its blocking power stronger by adding chemicals to it in the lab. 

Next, to make the peptide last longer in the body, they’ll attach it to parts of antibodies (proteins that protect the body from harm), creating what they’re calling a ‘nanobody’. They’ll also experiment with adding the peptide to other substances to improve its stability and effectiveness. 

After this, they’ll engineer beta cells to produce chemokine-blocking peptides of their own, and test if they’re working by exposing them to chemokines in the lab, and checking whether immune cells spot and attack them. Lastly, they’ll verify all their lab-based findings in mice with type 1 diabetes. 

How will this research help people with type 1 diabetes?

The peptides developed from tick evasin in this project could improve the success of beta cell transplants for people with type 1 diabetes, by giving them a built-in defence mechanism against the immune system. 

They could reduce the need for immunosuppressing drugs, which can make it harder for people to fight off infections, and can even increase the risk of developing cancer. Lowering the risk of side effects from immunosuppressants could ultimately lead to better outcomes for people with type 1 diabetes. 

Professor Shoumo Bhattacharya said:

“Our lab is looking to nature for new ways to treat inflammatory diseases. Ticks have evolved over millions of years to block inflammatory signals called chemokines. Chemokines cause beta cell inflammation which is important in the development of type 1 diabetes and can cause transplanted beta cells to fail.

“We are very excited to receive funding from the Grand Challenge, with which we aim to develop tick-inspired treatments to help people with type 1 diabetes. These treatments could improve the success of beta cell transplants, and prevent type 1 diabetes from developing.”

Led by Drs Craig Beall and Thomas Piers at the University of Exeter, this project will explore whether a type of cell found in the brain can help beta cells to make more insulin while hiding them from the immune system’s attack. Using ‘organ-on-a-chip’ devices, their approach could improve the outcomes of beta cell transplants. 

Background to the research project – brain cells for beta cells 

In type 1 diabetes, the immune system mistakenly attacks and destroys insulin-producing beta cells in the pancreas. But beta cells aren’t the only cells that make insulin, and the pancreas isn’t the only place in the body where insulin is made. 

Insulin is produced in the brain. There are at least six different types of brain cells that make insulin, and in type 1 diabetes these are hidden from the immune system attack. The cells all have different functions but the insulin they produce isn’t released in the right place or in high enough quantities to help manage blood sugar levels in type 1 diabetes.  

Dr Craig Beall and Dr Thomas Piers are investigating if a type of brain cell can be engineered to work together with beta cells to make lots of insulin, out of sight from the immune system. The hope is that this could help improve the effectiveness of beta cell transplants in people with type 1 diabetes.  

What will the team do in this project?

In the lab, Dr Beall and Dr Piers will grow clusters of insulin-producing brain cells and beta cells on a special plate called an ‘organ-on-a-chip’ device. They’ll recreate the conditions of type 1 diabetes, and test how these clusters react to sugar, nutrients, and treatments, compared to clusters of beta cells from human donors. 

They’ll also test how well blood vessels form around them on the organ-on-a-chip device as this will be important for keeping the cells alive when transplanted. 

How will this research help people with type 1 diabetes?

In current beta cell transplants, the immune system tends to attack transplanted beta cells, meaning some of the benefits of transplants are short-lived. Or people who’ve had transplants need to take drugs that dial down their immune system, called immunosuppressants. Dr Beall and Dr Piers’ project could lead to the development of new or improved beta cell therapies that can help people with type 1 produce insulin for longer periods without the need for immunosuppressant drugs. 

Dr Craig Beall said:

“We are really excited to have this funding from the Type 1 Diabetes Grand Challenge. This scheme really pushed us to harness brainpower to come up with the best possible ideas and to look for creative new concepts. The moonshot we’re aiming for is a cure that frees people with type 1 diabetes from insulin injections and immunosuppression, and this is the next step in that journey.“

In this project, Professor Hagemeyer and his team at Monash University, Australia will work to bring a new insulin delivery system closer to clinical trials. They have recently demonstrated that their first generation of insulin delivery system, called ‘Small Nano Sugar’, has a fast and efficient response to changes in blood glucose levels in animals with type 1 diabetes. 

What is Small Nano Sugar?

The Small Nano Sugar system carries insulin and a glucose-sensing molecule in tiny particles called nano sugars, which are injected under the skin. Insulin is then released from these particles, only when the body needs it. The insulin-carrying nano sugar particles react to very small changes in glucose, and release insulin only when glucose levels are outside a target range, without any input from the user.  

Prof Hagemeyer said:

“I’m thrilled to receive funding from the Type 1 Diabetes Grand Challenge for our project, together with our collaborators from the University of Melbourne and RMIT University. Our innovative approach leverages biocompatible, glucose-sensitive nano sugar particles to deliver long-lasting insulin therapy, significantly improving blood glucose management and quality of life for individuals with type 1 diabetes. The funding will accelerate further research towards clinical translation and first in human trials.”

What will Prof Hagemeyer do in this project?

In this project, Prof Hagemeyer will develop a second generation of this nano sugar-insulin system, based on advanced nanotechnology. The new design is supported by the team’s results from animals with type 1 diabetes and could bring the system a step closer to clinical trials in people with type 1 diabetes.  

 The team will check the system works effectively in realtime at mealtimes and throughout the day in primates with type 1 diabetes. Testing the system in animals will also allow the researchers to explore whether it can help protect against long-term complications of diabetes. 

How will this research help people with type 1 diabetes?

The next-generation Small Nano Sugar system has the potential to reduce the number of times people with type 1 have to inject insulin, reducing some of the burden of managing the condition. The system could also prevent dangerously low blood glucose, reducing the risk and fear of hypos, as well as the burden of multiple daily injections by keeping levels in a safe range for longer.  

Chemical engineer Prof Zhiqiang Cao and his team at the Wayne State University, USA aims to develop an even smarter insulin that can precisely manage blood glucose like a healthy pancreas.  

Developing smarter insulins

Trying to keep blood glucose levels in a target range is a constant challenge and burden for people with type 1 diabetes. Scientists are working to develop ‘smart insulins’ which can detect changes in blood glucose levels and respond by releasing the right amount of insulin at the right time. 

Prof Cao said:

“It is truly an honour to be recognised by the Novel Insulins Innovation Incubator funding panel. This award supports us in advancing our concept of glucose-responsive insulin injections. Our goal is to develop a product that addresses both mealtime and basal insulin needs, alleviating the constant management burden for people living with type 1 diabetes.”

What will Prof Cao do in this project?

Prof Cao previously developed a unique glucose-responsive insulin that overcame some of the issues linked to other smart insulin designs. Some smart insulins aren’t as powerful as currently available insulins, so people with type 1 diabetes need to take higher doses to have the same effect on lowering their blood glucose levels. 

In this project, the team plan to develop a novel insulin that addresses these problems, is more sensitive to changing glucose levels, and meets the needs of people living with type 1 diabetes better. Using a confidential new method, the team will optimise their design, checking its effectiveness and safety. They hope their insights will speed up the progression of ‘smarter’ smart insulins into clinical trials with people living with type 1 diabetes. 

How will this research help people with type 1 diabetes?

Prof Cao’s smart insulin would mean people with type 1 diabetes would experience fewer hypers and hypos, helping to lower anxiety about diabetes complications. It would also relieve people of the relentless burden of managing their condition, with fewer insulin injections and less blood glucose monitoring. 

Prof Zhen Gu and his team at the Jinhua Institute of Zhejiang University in China are designing novel insulins that respond immediately to rising blood glucose levels. In this project they will test a new kind of insulin that can be used either daily or weekly. Once injected, it forms a reservoir of insulin under the skin that is released in response to increasing blood glucose levels. 

Scientists are making strides in developing novel insulins that respond more quickly to rising in blood glucose levels without the need for close glucose monitoring. These glucose-responsive insulins mimic how the insulin-making beta cells work in people without diabetes. 

A new type of insulin

Prof Gu and his team are using a type of insulin called insulin/polymer complex as the starting point to develop a new glucose-responsive insulin. Prof Gu’s team has developed a method to combine insulin and polymer molecules.

Through experiments in cells and in mice with diabetes, the researchers have shown that the insulin/polymer molecule releases insulin when exposed to glucose and lowers glucose levels in the blood. By adding a safe glucose-sensing molecule to the insulin/polymer. Prof Gu’s team aims to create a novel insulin that will maintain blood glucose levels without causing hypos.

What will Prof Gu do in this project?

Prof Gu and his team will now improve their glucose responsive insulin by ensuring that all its components work together in the most effective way by fine-tuning the amounts of each of them. They’ll then test the glucose-responsive insulin to make sure it releases insulin correctly from the reservoir, especially when blood glucose levels are high. The team will also investigate how well the novel insulin can control glucose levels in cells and in animals with diabetes. 

By the end of the project, the researchers aim to have developed a high-quality glucose-responsive insulin that can be mass-produced in a cost-effective way. This will bring this novel insulin a step closer to clinical trials in people with type 1 diabetes. 

How will this research help people with type 1 diabetes?

The goal of this research is to create a novel insulin that effectively regulates blood glucose levels without causing them to drop too low. By speeding up insulin release from the reservoir after eating and slowing down when blood glucose falls below a safe point, this novel insulin could help people with type 1 diabetes to have steadier blood glucose levels, and lower anxiety around hypos. 

The researchers will also design the new insulin to be used less frequently than current insulins, reducing the time people with type 1 have to spend managing their condition. 

Prof Zhen Gu said:

“The clinical translation of this long-acting smart insulin will significantly enhance health and quality of life of people with type 1 diabetes.” He hopes that this type of insulin will one day be able to reduce the need for multiple daily insulin injections and limit the highs and lows in blood glucose that people living with type 1 diabetes experience.”

Professor Webber, a biomedical engineer at the University of Notre Dame, USA, designs medicines to mimic natural molecules in the body. Prof Webber and his team developed a ‘smart insulin’ comprising an injectable glucose-responsive reservoir.  

Designing insulin nanocomplexes

Professor Webber’s team has developed a smart insulin delivery system that uses tiny particles called nanocomplexes, which contain insulin. These nanocomplexes can be injected under the skin to create a reservoir of insulin. If glucose levels in the blood rise, insulin is automatically released from the stored particles into the bloodstream. 

This allows blood glucose levels to be managed in realtime, as less insulin is released when blood sugar levels are low. The team has shown that in pigs with type 1 diabetes, a single injection of the insulin nanocomplexes is enough to keep glucose levels stable for a whole week. 

What will Prof Webber do in this project?

In this project, Prof Webber and his team will continue to develop this smart insulin delivery system and test the function in pigs exposed to relevant real-life scenarios. They will explore more reliable ways to manufacture the insulin-containing nanocomplexes to allow them to be stored at room temperature.  

By collaborating with a non-profit company dedicated to developing of new treatments and cures, the team will also attempt to reduce the amount of the smart insulin needed in one daily injection to achieve the same blood glucose management. They will consider risk of hypos in response to exercise, eating vs not eating, and illness by testing it in pigs with diabetes. 

The research will help the team find out how quickly different doses of the new smart insulin bring down blood glucose levels at different times during the day, including at mealtimes, during exercise and when not eating.  

How will this research help people with type 1 diabetes?

This research project will bring smart insulins a step closer to clinical trials in people with type 1 diabetes. The smart insulin nanocomplex Prof Webber’s team is developing could one day help people with type 1 manage their blood glucose levels with fewer injections and a reduced risk of hypos. This would help people with type 1 to think less about their diabetes and more about living life to the full.  

Prof Matthew Webber said:

“Our work will develop and test new insulin formulations that offer simplified dosing schedules and which adjust their potency according to real-time blood glucose levels. Such technology will allow for a more autonomous therapeutic approach to treat type 1 diabetes, affording accurate blood glucose control while minimising side-effects.”

Prof Michael Weiss and his team at Indiana University, USA will develop and test a novel protein molecule that combines insulin and glucagon to help reduce the burden of blood glucose highs and lows for people living with type 1 diabetes.  

Glucagon and insulin

Unlike insulin, which helps remove glucose from the blood, glucagon is a hormone that stimulates the liver to release more glucose when levels in the blood run low. Prof Weiss and his team have designed and run initial tests on a molecule that combines insulin and glucagon.  

 By combining both hormones, the researchers hope their combined hormone can help prevent highs and lows in blood glucose and improve quality of life for people living with type 1 diabetes. They’ve tested the molecule in rats with type 1 diabetes and found that it can lower risk of hypos both at mealtimes and throughout the day.

What will Prof Weiss do in this project?

In this project Prof Weiss and his team will improve the design of the glucagon-insulin molecule to optimise time-in-range. They’ll run experiments in rats with type 1 diabetes to test how stable the dual hormone molecule is and confirm that it prevents both hypers and hypos.  

 They will also explore different ways to manufacture this insulin-glucagon molecule, to find the cheapest and easiest way to make large quantities, so it can be tested in human clinical trials in the future.  

Prof Weiss said:

“My colleague Prof Raimund Herzog at Yale and our team at Indiana University are most grateful to the Type 1 Diabetes Grand Challenge programme for supporting our efforts to prevent hypoglycemia in type 1 diabetes through the development of ‘smart’ insulin-glucagon fusion proteins. Thanks to Grand Challenge funding, we have the opportunity to test our ideas to enhance the quality of life for individuals with type 1 diabetes to make managing type 1 easier and safer to accomplish.”

How will this research help people with type 1 diabetes?

People with type 1 diabetes are constantly aware of the risk of hypos. Unlike other novel insulins, the aim of this research project is to protect against hypos by activating glucagon if blood glucose levels fall too low. 

 This research could pave the way to reducing highs and lows in blood glucose without the need for constant monitoring. It could be particularly helpful for people who often have hypos or don’t feel the symptoms of hypos (known as hypo unawareness). 

Prof Chou is a diabetes expert at Stanford University, USA who develops proteins to treat type 1 diabetes and other conditions. In this project, Professor Chou and his team will develop and test an ultrafast-acting insulin that’s only active when needed and could reduce the risk of blood glucose highs and lows in people with type 1 diabetes. 

Fast-acting insulins

Synthetic, fast-acting insulins have been developed that make it easier for people with type 1 diabetes to manage their blood glucose levels. Despite these advances, there’s still a delay between injecting insulin and the point it starts to bring down blood glucose levels.  

This delay is in part because current fast-acting insulins are hexamers (group of six molecules) which need to get separated from each other to form single insulin molecules. Even once separated, the single molecules still tend to cluster together in pairs, making it more difficult for them to do their job. 

What will Prof Chou do in this project?

Prof Chou and his team want to overcome the problem by designing an insulin molecule that doesn’t cluster, so it can get into the bloodstream even more quickly. The team’s design is based on insulin molecules found in a surprising place – venom from the cone snail, a type of underwater snail that uses insulin as a weapon. 

The novel insulin will be designed to mimic natural insulin produced in the pancreas in people without diabetes. This means that, compared to currently available insulins, this novel insulin will be released more quickly when blood glucose increases. When blood glucose levels fall, the insulin will also stop acting sooner, reducing the risk of hypos.  

Prof Chou said:

“Our proposed research project focuses on developing ultrafast acting insulin, which aims to significantly improve the quality of life for individuals living with type 1 diabetes. By providing faster and more precise glucose control, our work promises to enhance daily management, ultimately leading to healthier and more fulfilling lives for people with type 1.”

How will this research help people with type 1 diabetes?

The delay between an insulin injection and when it acts on glucose in the blood can mean people experience long blood glucose highs, particularly at mealtimes when blood glucose levels can increase quickly. Ultrafast insulins could help address this delay and reduce the risk of the diabetes complications linked to high blood glucose levels over a long time. The shorter duration of action would reduce the risk of insulin-induced hypos. These two improvements would enhance the quality of life for people with type 1 diabetes. 

Chemistry catching up with technology

We also need faster acting insulins, like Prof Chou’s, to fully close the loop in technology that links continuous glucose monitors with insulin pumps (known as closed-loop insulin delivery systems). Creating a faster insulin that also stops working sooner will enable better integration with closed-loop insulin delivery systems. Prof Chou’s ultrafast insulin would bring this technology closer to the normal functioning of a healthy pancreas as it would remove the need for the individuals to tell the system when they are about to exercise or eat.