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. 

Led by Professor David Hodson, at University of Oxford, Dr Ildem Akerman, at University of Birmingham, and Dr Johannes Broichhagen, at Leibniz FMP, this project will pioneer new approaches to make better beta cells ready for transplantation, protect the beta cells from an immune attack, and to regrow beta cells inside the pancreas. This research could speed up progress to making life-changing beta cell therapies available for people with type 1 diabetes.

Background to the research project

For people living with type 1 diabetes, a cure is likely to mean a combination of different treatments. We need to replace insulin-making beta cells that have been destroyed by the immune system, so people can start to make their own insulin again. And we need to protect new cells from an immune system that is primed to seek out and destroy them.

To reach this goal, scientists are pioneering methods to grow new beta cells in the lab and transplant them into people with type 1 diabetes. Scientists can do this using stem cells. Stem cells have the special ability to become just about any cell in the body, including beta cells. But at the moment, beta cells made from stem cells just aren’t as good at controlling blood sugar levels as real beta cells and don’t survive for long enough. Because of these challenges, scientists are also exploring treatments that could trigger new beta cells to regrow directly inside the pancreas.

Once we can give people with type 1 working beta cells, we also need to protect them from the type 1 immune attack. Treatments, called immunotherapies, are designed to do this by retraining the immune system.

Professor Hodson, Dr Akerman and Dr Broichhagen are hoping to make transformational progress in all three of these areas with the help of two molecules known as incretin receptors. These receptors are found on the surface of beta cells and act as on-off switches to help control the release of insulin. Scientists have already harnessed their potential and developed type 2 diabetes drugs that target the receptors, to help people lower their blood sugar levels. They think the receptors could be key to unlocking major progress in type 1 diabetes beta cell therapies too.

What will the team do in this project?

1. Produce better functioning and longer lasting beta cells made from stem cells.

The team has previously discovered that around 20% of lab-made beta cells have incretin receptors on their surface, and that these are better at producing insulin than beta cells without it.

First, the team will develop a way to find the cells that have the receptors, using a technique called cell sorting. If this method was used to analyse a smoothie it would be able to tell us what fruits were used to make it and locate them. Then to check how well they are working, they’ll transplant the receptor beta cells into mice with type 1 diabetes and test if they work better than beta cells without these receptors.

2. Deliver an immunotherapy straight to the surface of the beta cells, to help better shield them from an immune attack.

The team will design an immunotherapy that will seek out and bind to incretin receptors at the surface of beta cells, so the treatment goes straight to where it’s needed. They’ll investigate if this precision delivery makes the immunotherapy more effective at slowing or stopping an immune attack, and brings fewer side effects, in mice with type 1 diabetes.

3. Coax other cells in the pancreas, called alpha cells, to transform into beta cells.

Alpha cells produce a hormone that raises blood sugar and are left unharmed by the type 1 immune attack. They carry incretin receptors on their surface. The research team will modify existing drugs that target incretin receptors to carry cargo that works to change the identity of an alpha cell into a beta cell.

How will this research help people with type 1 diabetes?

Beta cells therapies have the potential to transform how we treat type 1 and to form part of a cure. Selecting for the top performing lab-made beta cells and arming them with a protective immunotherapy will be key in moving transplants from the lab towards the clinic. While enticing new beta cells to grow inside the body could give us another way of restoring people with type 1’s own insulin production.

Bringing back beta cells would allow us to say goodbye to insulin injections and pumps, reduce the need for constant blood sugar monitoring and help prevent diabetes complications.

Professor David Hodson said:

“During the past decade, a lot of our work has focused on insulin-boosting molecules found on beta cells, called incretin receptors, which have become major drug targets for type 2 diabetes and obesity therapy. Using our knowledge and innovative technologies, we will now translate our work in type 2 diabetes and leverage the potential of incretin receptors in the type 1 diabetes space.

“We’ve developed an ambitious three-prong research programme that spans beta cell replacement, protection and regeneration, so as to give us the best chance of driving discoveries that could make these treatments available for people living with type 1 diabetes.”

Professor Francesca Spagnoli and Dr Rocio Sancho at King’s College London, together with Professor Molly Stevens at University of Oxford, hope to unlock the full potential of transplants of insulin-making beta cells. They’ll innovate ways to keep cells safe from harm once they’re transplanted into someone with type 1, so we can move closer to the day when beta cell transplants can free people from the relentless task of managing type 1 diabetes.

Background to the research project

Scientists are using stem cells to develop treatments to replace the beta cells that have been destroyed in people living with type 1 diabetes. Stem cells have the special ability to shape-shift into other types of cells in the body, including beta cells.

Small clinical trials of stem cell-turned beta cell transplants are now underway and are showing early promise. But after being transplanted into people with type 1 diabetes, new beta cells struggle to survive and gradually lose their ability to make enough insulin and tightly control blood sugar levels.

Using expertise from different fields including biology, immunology and engineering Professor Spagnoli, Dr Sancho and Professor Stevens will lead a team to tackle these challenges and give lab-grown beta cells the tools they need to survive and do their job after transplant.

What will the team do in this project?

The team will explore ways to both create tougher beta cells that can better withstand their post-transplant environment, and to make this environment friendlier.

1. 1. They’ll replicate the supportive environment found in a healthy pancreas by coating their lab-grown beta cells with protective gels that can help them stay safe and strong.
   2. They’ll use nanoparticle technology to deliver ingredients that can give the cells a survival boost after transplantation and protect them from an immune system attack.
   3. They’ll develop a transplantation device that beta cells can live inside. This protective ‘cage’ will provide the cells with the right levels of oxygen they need to survive and make them more resistant to their hostile surroundings. They’ll transplant this device containing their reinforced beta cells into rats with type 1 diabetes to investigate if the cells manage to survive long-term and produce enough insulin to control blood sugar levels.

How will this research help people with type 1 diabetes?

Creating the ideal conditions that keep transplanted beta cells alive and kicking could help us move quicker towards a new era in type 1 diabetes, where people are free from the burden of taking insulin, the fear of hypos and complications, and the mental load of self-managing their blood sugar levels.

Professor Francesca Spagnoli said:

“The Type 1 Diabetes Grand Challenge funding means we can explore new avenues in diabetes research. We’ll be able to start moving some of our discoveries closer to clinical applications and drive improvements in cell replacement therapies, which could ultimately cure type 1 diabetes.”

Professor Shareen Forbes, at University of Edinburgh, and Dr Lisa White, at University of Nottingham are exploring better and more innovative ways to transplant islets, clusters of pancreas cells, into people with type 1 diabetes to enable them to make their own insulin. This could pave the way for wider use of this life-changing treatment, while also making islet transplants much more effective.

Background to the research project

In an islet transplant, clusters of cells (called islets) from a donor pancreas are transplanted into someone with type 1 diabetes and start to produce insulin. They’re currently offered to some people with type 1 diabetes who have severe hypos and no awareness of them. However, usually about 60% of the donor cells die soon after transplant.

This means lots of donor islets are needed to have an impact on blood sugar levels. But with a limited number of donor pancreases available for islet transplantation, very few people with type 1 diabetes can currently benefit.

What’s more, islet transplants aren’t as effective as they could be. They rarely allow people to produce enough insulin to stop insulin therapy. And people need to take anti-rejection drugs to prevent their bodies rejecting the donor cells, which can bring serious side-effects.

Scientists are looking at ways to improve the benefits and availability of islet transplants, so they can become part of a cure for type 1 diabetes. Professor Forbes and Dr White think drugs packaged inside microparticles could provide an answer. Microparticles are tiny particles that help to protect a drug from the harsh environment in the body and deliver it to exactly where it’s needed. If drugs that keep islets healthy and protect them from the immune system could be transplanted alongside islets, it could help them to survive and thrive for longer.

What will the team do in this project?

Professor Forbes and Dr White will package microparticles with immune-altering and other drugs to improve the survival of transplanted islets. They will test different combinations of drugs in islet transplants in mice, to see which work best to help islets survive and control blood sugar levels.

The team will then run experiments to investigate how to scale up the dose of the drugs and how the treatment might work in humans.

Finally, they will check if the most promising drug microparticle combinations also work to protect beta cells that have been grown in the lab from stem cells.

How will this research help people with type 1 diabetes?

At the moment only a tiny fraction of people living with type 1 diabetes are eligible for islet transplants. And they’re far from a permanent or perfect fix.

If the team can improve the survival of donor islets it could unleash the benefits of islets transplants – making them much more effective at managing blood sugar levels, eliminating the need for anti-rejection drugs and opening them up for more people with type 1 diabetes.

In the longer-term, their discoveries could also be used to radically improve transplants of lab-made beta cells. This would entirely remove the supply problem of using donor cells, so that in the future everyone with type 1 diabetes could benefit from transplants.

Professor Shareen Forbes said:

“I hope the Grand Challenge’s investment will give people living with type 1 diabetes hope that a cure can be achieved in their lifetime.

“The funding has allowed scientists from diverse fields to come together in this project with a common goal of doing some truly innovative research that will advance the field. By improving the benefits of human pancreas cell transplants, and in time transplants using stem cells, we hope to contribute towards a future where people with type 1 diabetes can live a life free from insulin injections.”

Professor Shanta Persaud and Dr Aileen King are world-leading experts at studying how insulin-producing beta cells work and develop in humans. They’ll use their specialised knowledge to run state-of-the-art experiments and find ways to improve methods to engineer new beta cells in the lab, so they act and react more like real human beta cells. This project could help to accelerate progress towards life-changing new treatments that restore insulin production in people with type 1 and bring us closer to a cell-based cure for the condition.

Background to the research project

People with type 1 diabetes rely on insulin injections or pumps to replace what the immune system has destroyed. While insulin therapy is lifesaving, current insulins don’t come close to the minute-to-minute adjustments that beta cells make to manage blood sugar levels.

Scientists have been trying to find ways to give people with type 1 new beta cells, by making them in the lab from stem cells and transplanting them inside the body. Although lots of progress has been made in recent years, lab-made cells just aren’t as good at producing insulin or responding to changing blood sugar levels as real beta cells are.

Lots of what we know about turning stem cells into beta cells is based on how beta cells develop in mice. But Professor Persaud and Dr King have been studying human pancreas development and want to harness this knowledge to make better performing beta cells that are well equipped to survive transplantation.

What will the team do in this project?

Professor Persaud and Dr King will lead a team to:

1. Improve the process of turning stem cells into beta cells.

They’ve discovered that cells that support nerve cells (called Schwann cells) may also help support beta cells. They will carry out tests to see if Schwann cells could improve the ability of stem cells to transform into functioning beta cells.

2. Make sure lab-grown beta cells produce the right amount of insulin.

Once beta cells have been made, the team must make sure they are an elite class of insulin producers. They’ll run tests to see what type of support, nutrients and special molecules can help the newly made cells work even better.

Next, they’ll use state-of-the-art techniques to rigorously test if the lab-made beta cells are really acting like real beta cells. This includes looking at how the lab-made beta cells use oxygen, store insulin and respond to rising blood sugar levels.

3. Give lab-grown beta cells the best chance of surviving after transplantation.

The team will coat clusters of lab-grown beta cells with survival boosting molecules, by a process called nanoencapsulation, and test if this helps them survive transplantation better.

How will this research help people with type 1 diabetes?

Having an unlimited supply of elite beta cells ready for transplantation could mean a future where people with type 1 diabetes never have to think about their blood sugar levels or insulin, because their beta cells are doing it for them. While transplants would also help to reduce the risk of developing diabetes complications.

If successful, this project will turbo charge progress towards clinical trials of transplants using new and improved lab-grown lab cells, and move us closer to a cure.

Dr Aileen King said:

“People with type 1 diabetes have to constantly think about their blood glucose levels and adjust their insulin doses in response. Our aspiration is to produce fully functioning beta cells suitable to implant into people living with type 1 diabetes, which do this on their behalf.

“This would be transformative for people with the condition, as it would restore the body’s minute-to-minute insulin production that is required to carefully control blood glucose levels – reducing the risk of dangerous blood sugar lows and long-term diabetes complications, while also reducing the huge psychological impact of living with diabetes.”