Advances in the treatment of type-1 diabetes

Alternative treatments for type-1 diabetes may become a reality in the near future, say Professor Steve Bain and Dr David Price.

Type-1 diabetes is a chronic disease that typically presents in children and young adults. It is caused by autoimmune destruction of the insulin-producing pancreatic beta cells and leads to an absolute deficiency of insulin.

The cause is unknown but involves a complex interaction between genetic and environmental factors. Insulin injections have been the mainstay of treatment, allowing survival but having complications affecting the eyes, kidneys and feet.

Diabetes is the major cause of blindness in the working population of the UK, the most common cause of end-stage renal disease and leads to more lower limb amputations than any other disease.

Islet cell transplantation
The replacement of the body's capacity to produce insulin has been a goal of research for many years. Initially the focus was on whole-organ pancreas transplantation and research continues with a target population of type-1 diabetics who require a donor kidney.

In 2000, a group in Edmonton, Canada published what seemed to be a ground-breaking study describing seven patients who had been rendered insulin-independent by the transplantation of pancreatic islets.

The advantages of such a technique were obvious, with minimal surgical intervention and no need to deal with the exocrine function of the whole organ. The advances the group had made related to successful extraction of islet tissue from cadaver pancreata and a relatively non-toxic immunosuppressive regimen.

However, an international trial of the Edmonton protocol published in the New England Journal of Medicine made rather depressing reading. The collaborative group of nine centres screened approximately 2,000 subjects with type-1 diabetes, to identify 149 eligible patients with at least five years' duration of diabetes and recurrent hypoglycaemia.

Of these, 36 subjects received a total of 77 islet cell infusions and all but one was followed for two years. Twenty-one patients reached insulin independence but only five patients remained so at two years. The trial was projected as a success but it did not support the initial optimism.

UK results have been similar, with no patients being rendered totally independent so far.

Other areas of transplantation such as live-related pancreas donation, islet encapsulation and xenotransplantation (using animal islets) remain in the research domain.

Even if successful, islet cell transplants will be limited by the lack of suitable donor organs and this has been a stimulus for stem cell research.

The aim is to produce cell lines that can develop into fully functioning islets. This research is still in its infancy and may be technically impossible.

Oral insulin
Oral insulin has long been dismissed as a pipe dream because gastric acidity renders insulin inactive. However, at least two companies claim to have created a delivery system that protects insulin from enzymatic digestion and facilitates its absorption across the intestinal mucosa.

There is little in the peer-reviewed literature to allow an adequate scientific scrutiny. There may be a degree of over-hyping aimed at securing funding, but perhaps such cynicism will prove unfounded.

Inhaled insulin
Inhaled insulin, such as Exubera, was marked for use in Europe in January 2006 and a further two inhaled insulins are going through phase III clinical trials. Inhaled insulins appear to have an equivalent effect to prandial, rapid-acting insulin analogues but do not remove the need for a long-acting basal insulin, which still needs to be injected. The perceived excess cost of Exubera has led to interventions from NICE, with guidance limiting prescription to type-1 patients with poor diabetic control due to a needle phobia, or severe and persistent problems with injection sites.

Issues of safety remain. Inhaled insulins appear to cause a reduction in lung function, manifested by a fall in carbon monoxide diffusion capacity.

Although these changes are reversible, the effects of long-term exposure of alveoli to insulin needs to be monitored and precludes the use of inhaled insulin in children.

Amylin and glucose
Amylin is co-secreted with insulin by the beta cells and affects glucose levels by slowing gastric emptying, suppressing post-prandial glucagon secretion and regulating food intake.

Amylin cannot be used clinically since it is poorly soluble but the synthetic analogue pramlintide is marked in the US as an adjunct to mealtime insulin.

Studies in type-1 diabetes show small but significant reductions in HbA1c levels in the face of reduced insulin requirement and weight reduction.

There is, however, an increased hypoglycaemia risk.

Pramlintide has to be injected subcutaneously at a separate site to the pre-meal insulin injection. It also partly negates the benefits of rapid-acting analogue insulins by delaying the post-prandial peak until after their maximal activity. It is therefore doubtful that pramlintide will have a big impact on the management of type-1 diabetes.

Insulin pumps
Insulin pumps are portrayed as the modern treatment modality and in the US, around half of healthcare professionals with diabetes choose this option.

Insulin pumps were first trialled in the 1970s, but over the past decade, continuous subcutaneous insulin infusion has become a feasible option and pump use will presumably increase in the UK, despite the dead hand of a NICE technology assessment.

The advantages of continuous insulin administration are less variability in insulin levels and ease of variation of insulin dose. These mean a substantial reduction in severe hypoglycaemia, although the benefits in HbA1c levels are less dramatic, especially in those with reasonable control on multiple injections. But quality of life appears to be better than for those who inject frequently.

Not all patients are suitable for a pump. Some are unable to perform the techniques, others are 'psychologically unsuitable', while many simply prefer multiple injections.

There are also issues that will stretch limited resources, apart from the costs of hardware and consumables. These include the need for detailed knowledge of carbohydrate values and frequent self-monitoring. This may be resolved by a closed-loop delivery system, where insulin dose is automatically adjusted by blood glucose levels.

The US Food and Drug Administration has approved an integrated real-time continuous glucose monitoring (CGM) system and insulin pump.

An early prototype of the system, which was not fully integrated, was tested in 20 volunteer patients who had type-1 diabetes.

Subjects reduced HbA1c by a mean of 1.1 per cent, with two-thirds achieving an HbA1c <7 per cent.

More recent studies have examined closed-loop insulin delivery coupling, an implanted insulin pump that infuses insulin intraperitoneally with an intravenous enzymatic glucose sensor.

This is an exciting area of development but will probably have limited patient uptake in the immediate future.

Glucose monitoring
A useful advance would be an efficient way of performing blood glucose monitoring without the need for painful fingerprick testing.

Early versions of this technology have passed the proof-of-principal test and are commercially available in the UK (the Glucowatch device).

However, there are issues around cost, reliability and adverse effects.

Glucowatch tended to fail on moist, cool skin (as might be expected during a hypo) and caused long-lasting skin irritation in many subjects.

The area of non-invasive testing is rapidly expanding and a recent review highlighted 14 different technologies under development with over 12 instruments approaching approval. Non-invasive testing will become a possibility in the next five years, at which point further battles with NICE will no doubt commence.

Professor Bain is professor of medicine (diabetes) at the University of Wales and Dr David Price is consultant physician at Swansea NHS Trust

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