Delivering insulin in a smart way for diabetics

Since news broke that Dr John Fossey was embarking on a groundbreaking research project to develop a ‘smart insulin’ delivery service for type 1 diabetes sufferers, he has received many letters from well-wishers.

The level of public interest has taken him somewhat by surprise – ‘I’m a bit behind in replying to everyone’ – and added to the sense of responsibility he feels to translate basic science into treatment that could affect the lives of millions of people, especially children.

John, Senior Lecturer in Synthetic Chemistry, and his Birmingham team have won funding from the Juvenile Diabetes Research Foundation (JDRF) to support two full-time post-doctoral researchers for two years in their efforts to develop glucose-responsive insulin, a type of injectable insulin preparation that responds to glucose levels in the blood.

The lab-based project involves creating balls of a special gel that contain pockets of insulin, which dissolve in high concentrations of glucose. The long-term goal is for these balls to be injected, and, a bit like a bath bomb in water, break up in the presence of high glucose levels, releasing the pockets of insulin.

The success of the project could lead to diabetics no longer having to carry out blood tests, work out the right dose of insulin and then inject themselves. The ‘smart insulin’ delivery service would do it all automatically.

The synthetic ‘click chemistry’ behind the emerging therapy has been used by John and his colleagues at the School of Chemistry. Their third and most recent paper in this area, entitled ‘Glucose selective bis-boronic acid click-fluor’, was published in ChemComm – it even made the issue’s front cover – and recently won the College’s Paper of the Month award.

Co-written by PhD student Wenlei Zhai and Dr Louise Male, the School’s X-Ray Diffraction Facility Officer, the paper focuses on the team’s work in making a molecular sensor that recognises selectively another molecule, in this case glucose.

‘Glucose is one of many sugars,’ explains John. ‘It’s very easy to make a molecule that recognises any sugar, but very difficult to make one that can differentiate between two different types of sugar, such as glucose and fructose.’ This is because although the two sugars are different in shape, the differences are extremely subtle.

Wenlei, who has since returned to his native China to take up a post-doctoral position, explains how crucial progress was made by introducing a bis-boronic acid motif for glucose recognition: ‘The glucose binding affinity and selectivity was optimised by finely tuning he space between these two boronic acid groups. Moreover, a coumarin fluorophore was integrated into the optimised receptor and a novel glucose-selective fluorescent sensor was designed and prepared following the synthetic strategy developed by us.’

Louise, who runs the School’s single crystal X-ray diffraction service, which is used by researchers across campus and from outside the University, was pivotal in obtaining the crystal structures, which, says John, ‘allowed us to learn something about the sensors’ shapes and selectivities, which was crucial’.

Although the researchers aren’t the first to make these glucose-selective molecules – the work that inspired this recent publication was born in Birmingham: Professor Tony James, now at the University of Bath, first reported on this kind of molecule when he was at Birmingham 20 years ago – the current Birmingham team are the first to make them using click chemistry.

Click chemistry is a term introduced by Nobel Prize-winner Professor Barry Sharpless in 2001 to describe reactions that are high yielding, wide in scope, create only by-products that can be removed without chromatography, are stereospecific, simple to perform, and can be conducted in easily removable or benign solvents. John describes it as ‘a simple chemistry’ because of the easy assembly process and its cost-effectiveness.

As well as using this method to make glucose-selective molecules, John is already looking ahead to the possibility of making selective molecules for other sugars.

‘These could be markers for other critical diseases. For example, often there are biological markers of diseases in the bloodstream that could indicate various types of cancer. I’m not saying we have made a single-molecule cancer detector, but we have made a glucose-selective receptor that demonstrates a synthetic protocol – a platform technology for single-molecule sugar-sensored design.

‘But the next big challenge for our team – which will be ten-strong by the next academic year – is to exploit the glucose selectivity we have discovered and take the glucose sensing technology to the next level in terms of insulin delivery. It’s perhaps ten years away, but we hope our work will translate to clinical use to manage insulin levels for people with diabetes, particularly children.

‘There is a challenge to be met, one that affects people’s daily lives, so we have a burden of responsibility. We have to do our best to see if this will work, and we have only two years to do it in. The pressure is on.’

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