Feature

Delving into Diabetes

On-going research into a new form of treatment for diabetes holds hope for the 150,000 New Zealanders who suffer from the condition.

Tom Mulvey

A variety of approaches to treating diabetes have been used over the past 70 years, and researchers at Auckland University's Schools of Biological Sciences are working on adding another weapon to the arsenal.

Diabetes involves problems caused by the failure to regulate the metabolism of glucose by the hormone insulin; in some case not enough insulin is produced by the pancreas, in others the body fails to make use of the insulin available. There are two major sub-types of diabetes, distinguished by whether insulin injections are required to control the condition.

Type I, or insulin-dependent diabetes, as its name suggests, involves regular injections of insulin. It is also called juvenile onset diabetes because it affects mainly the young -- people under the age of 20. In this form of diabetes the pancreatic beta cells are destroyed by autoimmune T-cell mediated attack, resulting in life-threatening insulin deficiency, hence the need for specific control. About 15,000 people in New Zealand suffer from Type I diabetes.

Type II, or non-insulin-dependent diabetes, is also known as maturity or adult-onset diabetes as it occurs in the older population. It is relatively common, with around 135,000 cases in New Zealand. The causes of maturity-onset diabetes are obscure, but two main defects are recognised: the failure of insulin to act normally in peripheral tissues (insulin resistance), and impaired insulin secretion.

The introduction of insulin replacement therapy in 1921 was a dramatic medical breakthrough for treating Type I diabetics. Insulin therapy has not solved all the problems of juvenile diabetic patients, who face the continual danger of hypoglycaemia (a lack of blood sugar), a high probability of serious long-term complications, and a markedly reduced life expectancy. It is believed that these complications are caused in large part by excessive blood glucose levels. These can result in damaging glycosylation and cross-linking of many key proteins and the abnormal build-up of glucose metabolites in certain tissues.

Type II diabetics were aided by the introduction during the 1950s of sulphonylureas and metformin, two classes of oral hypoglycaemics which are drugs that serve to reduce the level of blood sugar. In addition, many patients use insulin supplementation. However, these treatments are not regarded as adequately effective in controlling the disease, its progression or its complications. While the development of maturity-onset diabetes clearly has a genetic component and is exacerbated by lack of exercise and eating too much, there is clearly still much to learn about the pathology of diabetes and associated disorders such as obesity and hypertension.

The Hunt for New Approaches

A New Zealand doctor, Garth Cooper, concerned by the difficulties of achieving good management for many of the diabetic patients in South Auckland, asked himself whether something fundamental had been missed by diabetes researchers. In 1985 he was awarded a Nuffield Scholarship at Oxford University and there he set out to investigate the pancreatic amyloid deposits that we now know are characteristic of maturity-onset diabetes but which are not seen in juvenile-onset diabetes.

These deposits had been discovered in those parts of the pancreas known as the islets of Langerhans (small collections of endocrine tissue that mainly comprise insulin-secreting beta cells and glucogen-secreting alpha-cells). Although originally described in 1901, the deposits were largely ignored or regarded as just pathologic "grave-stones" of aging islets.

In the face of considerable scepticism about whether it would be feasible or worthwhile, Cooper set out to determine what these amyloid deposits were made of. His statistical analysis of new data led him to conclude that these deposits held an important clue about the pathology of Type II diabetes. He continued his research at the Medical Research Council Immunochemistry Unit where there was the expertise and equipment needed to support this enormously difficult chemical task.

After many months of intensive work, Cooper and his colleagues isolated and chemically characterised minute amounts of a new 37-amino-acid peptide, which he called amylin. Amylin turned out to have structural features consistent with it being a hormone, and its gene was found to code for a sequence typical of pro-hormones. Microscopic and functional studies showed that amylin was made in and secreted from beta cells along with insulin. In addition Dr Cooper showed that it was capable of causing insulin resistance in muscle tissue, as is seen in maturity-onset diabetes.

Amylin Connection

It has now been shown that amylin secretion, like insulin secretion, is absent or markedly deficient in juvenile-onset diabetes, and remains deficient in patients on insulin replacement therapy. Cooper suggested that amylin replacement held the key to preventing the major glycaemic swings and hypoglycaemic episodes that are a great concern for patients on insulin replacement, and that Type I diabetics using amylin replacement would be able to maintain their blood glucose levels closer to normal.

The consequences of all this could be that the rate of diabetic complications, such as damage to the kidneys, retinas, nerves and reduced life expectancy, would be lessened, probably considerably. In 1987, Cooper co-founded a pharmaceutical company, Amylin Pharmaceuticals, with the object of testing amylin (or an almost identical homologue) replacement in Type I diabetics, and also with a view to developing other molecules which could be useful in addressing the symptoms in Type II diabetes.

Amylin is produced in excess in adult-onset diabetes. Cooper carried out a series of experiments which showed that amylin could cause insulin resistance in skeletal muscle tissue. In addition, our research group in Auckland has shown that human amylin can form needle-like structures (fibrils) which causes death of islet b-cells when placed next to them. This could account for the death of islet b-cells which is an on-going development seen in people with Type II diabetes when amylin deposits form next to the islet cells. Ultimately this phenomenon leads to destruction of b-cells, worsening of the condition and insulin dependence.

What new types of therapy might emerge from present research? Extensive clinical trials are being conducted in the United States and Europe to see if an improvement in blood glucose control can be achieved by replacing amylin as well as insulin in Type I diabetics. A trial of 215 Type I diabetics (double blind, placebo controlled) reduced their blood glucose by 1.4 mmol/L test versus placebo. The effect on plasma fructosamine levels was an average reduction of 62 mmol/L. This would correspond to a reduction in diabetic-caused complications of more than 50%. Additionally, there were no drug-related hypoglycaemic episodes.

Amylin Pharmaceuticals, in combination with Johnson and Johnson, are conducting Phase III trials in the US which are expected to be completed by the end of this year. FDA filing on the product should be completed by the end of 1998, and the combined insulin/amylin available by the end of 1999.

Dr (now Professor) Cooper returned to New Zealand in 1993 and set up a research group in Auckland University's School of Biological Sciences with a view to continuing his work here. Both Amylin Pharmaceuticals and his research team at Auckland University are independently working on blockers to reduce the effects of amylin. This is aimed at helping those who experience carbohydrate intolerance because of insulin resistance as well as those who have full Type II diabetes. In addition, investigations are under way to block the effects of amyloid deposits within the pancreas which results in the destruction of the islet b-cells.

The goals of this work are to treat the condition and stop it worsening. Clinical trials for some of these treatments are two to three years away; for some others, somewhat later. Group members are focussing their efforts on many diverse projects including determining the molecular basis of the mechanism by which b-cells are killed, clarifying the way in which amylin causes insulin resistance in skeletal muscle and studying how amylin is formed and secreted from the b-cells. The good progress of this work relies on being able to attract on-going funding.

Tom Mulvey is a member of a research team working with Professor Cooper at Auckland University.