Post date: 
Friday, 5 September 2014

Diabetes may be on the increase, but rates of diabetes-related eye disease are down. Radhika Holmström investigates diabetic retinopathy and some of the treatments on offer.

Earlier this year, there was one piece of diabetes good news: rates of diabetic eye disease are actually dropping, to the point where it is no longer the leading cause of blindness in adults of working age across England and Wales. It is even better news when seen against a backdrop of the sheer number of people with diabetes – more than 3.2 million adults in the UK, or six per cent of the adult population, according to the charity Diabetes UK.

How diabetes affects the body overall

Diabetes comes in two forms. People with Type 1 are completely unable to produce insulin, the hormone produced by the pancreas, which (among other things) controls glucose levels in the bloodstream. Type 1 usually develops during childhood or early adulthood (which is why it is sometimes referred to as ‘juvenile’ diabetes); and it is an autoimmune condition. 

People with Type 2, which is more prevalent (and is enormously prevalent in people of South Asian origin) either do not produce enough insulin or cannot absorb properly the insulin they do produce. There are genetic factors – people with South Asian, African, African-Caribbean or Middle Eastern heritage are particularly prone to it – but it is also linked to obesity, which is the main reason why it is increasing so rapidly.

People with both types of diabetes need to change their diet. People with Type 1 usually need insulin injections, and those with Type 2 may require medication to improve the body’s own insulin production and, if this doesn’t work, insulin injections. 

The effects on the vision

Historically, about 50 per cent of the people who have had diabetes for 10 years, and more than 85 per cent who have had diabetes for over 20 years, have developed some sort of retinopathy – although this may of course be on the decrease now.

Either type of diabetes can affect the eyes because high blood sugar levels can weaken the blood vessels – and the network of vessels supplying the retina is extremely delicate. The exact mechanisms are the subject of intense scrutiny – and, in fact, this is where quite a lot of the research is being carried out. 

Professor Alan Stitt is the Scientific Director of the Centre for Vision and Vascular Science (CVVS) at Queen’s University, Belfast. He explains: “A lot of my research over the past 10 to15 years has been looking at ‘advanced glycation end products’ or AGEs. These are chemical products that accumulate in everyone as we get older, and we know that there is a relationship with higher glucose levels. AGEs are also linked to inflammation, which is now understood as one of the underlying mechanisms in diabetic retinopathy. It’s low-level, but nevertheless immune modulators are released and over the course of up to 30 years of diabetes, that really starts to provoke a level of damage.”

David Bates, Professor of Oncology, Faculty of Medicine and Health Sciences at the University of Nottingham, explains another angle.  “There’s evidence that high glucose itself can be toxic to the cells that form the blood vessels. In addition, there seems to be an effect on the surface of the endothelial cells – the sugary coat that lines them can be affected by too much sugar, resulting in cell death.”

Whichever the cause, there is a further damaging knock-on effect, he continues. “The loss of blood cells leads in turn to hypoxia (lack of oxygen) and the body’s response is to make more blood cells which produce vascular endothelial growth factor (VEGF). Of the different forms of VEGF, normally we need to produce a balance of VEGF165A and 165B. The A form makes blood vessels grow, and it also makes them leak – which can be very useful at the back of the eye, where we need a high fluid flow to carry away waste products, but not in the macula. The B form blocks the A form to keep the balance correct, and it also prevents cells dying. But when cells do become hypoxic, they stop making the B form and only produce the A form.” 

It is hardly surprising that all these different changes impact on the eye. The earliest visible change to the retina is known as background retinopathy. Even before the sight is affected, the capillaries in the retina become blocked, may bulge slightly and may leak blood and/or fluid. The next stage is maculopathy, or macular oedema, as all the leaking causes the cells in the macula to swell. People with this condition start losing part of their central vision, which means it is harder for them to recognise features or fine detail. However, they very rarely lose all their sight.

After that, there is proliferative retinopathy, as the background retinopathy develops and large areas of the retina are deprived of a proper blood supply because of blocked and damaged blood vessels. On top of the other effects of hypoxia, the new blood vessels are very delicate and bleed easily, leaving scar tissue that starts to shrink and pull on the retina, distorting it and sometimes even detaching it.

Treatments

Treatments for the different forms of diabetic eye disease have improved dramatically in the past few years, although they are still not a guaranteed solution for everyone. Until relatively recently, the main treatment was laser surgery; people with very advanced proliferative retinopathy, with repeated haemorrhaging from the vitreous or a great deal of retinal scarring might also be offered a vitrectomy, which removes the vitreous humour in front of the retina and seals the leaking blood vessels. 

Laser surgery is still being used and indeed the techniques are improving quite significantly too, so that the treatment is immeasurably quicker, more accurate and less painful than it was a couple of decades ago. It is not the only story, though. The big breakthrough in recent years is anti-VEGFs, to tackle the problems that Bates outlines. This may be done through an implant (Iluvien), which was finally approved by the National Institute for Health and Care Excellence (NICE) after some controversy in 2013, or, more commonly, through injections into the eye in the same way as treatment for age-related macular degeneration (AMD). 

In addition to the existing treatments, Bates and his colleagues are looking at ways to get the natural VEGF expression balance correct – possibly by using gene therapy – and also at options for delivering the medication through drops rather than injections (which would also take the burden off clinics). “The idea is now to get drops using chemicals that inhibit the A form, by blocking the receptor, or the signals transmitted by the receptor, or switching the gene mechanisms to restore the balance.”

However, anti-VEGFs have a surprisingly high failure rate, Stitt points out. “Probably nearly around 40 per cent of patients don’t get a benefit, and we don’t know who those people will be until they’ve had around a year of expensive and invasive therapy.” Even the successful 60 per cent need regular injections for life – which can mean for around 70 years or more (whereas patients with AMD are by definition a lot older when they develop the disease). “And the fact they need to go on getting injections underscores the fact that you’re addressing the end point, not the cause,” he adds. He and members of his department are looking at different ways to intervene in the disease progression at an earlier stage. 

One strand of work is exploring different ways to stop the AGEs or related chemicals build up in the first place in order to block inflammation at an early stage. This has previously been done using steroids, but for a number of reasons (including raised intra-ocular pressure) it is not broadly recommended. Another is looking at seeing if a version of the naturally occurring protein erythropoietin (EPO), which helps control the production of red blood cells, could offer protection. “The key is to get to the disease early enough.”

An ongoing crisis

The research into this complex disease – and the complex chemistry of the eye – is extremely encouraging. At the same time, though, rates of diabetes are still increasing; it has become a major national health crisis. Even if this work arrests the damage on the eye, the disease will still damage a huge number of other organs and tissues. Above all, it’s the underlying cause that needs to be tackled.

 
 
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