Preventing insulin dependent diabetes mellitus.

The ultimate goal for those who care for people with insulin dependent diabetes is prevention. This seemed a futile quest until the 1 970s when the aetiology ofthe condition began to be unravelled. Insulin dependent diabetes mellitus was shown to be an autoimmune disorder with a genetic basis, strongly associated with the class II alleles DR3 and DR4. This led to a series of studies of immunosuppression, mainly using cyclosporin,' 2 but also azathiaprine3 and steroids, in patients newly presenting with insulin dependent diabetes mellitus. Cyclosporin proved relatively effective in delaying insulin dependence and inducing prolonged remissions. It was particularly useful within four weeks of diagnosis and in patients with moderate symptoms and no weight loss.4 The lack oftotal success is not surprising given that more than 90% of [B cells have been destroyed by the time of diagnosis. Intensive insulin treatment may also prolong remissions, presumably through decreasing "glucotoxicity." But there are several problems with these approaches. Firstly, they come too late in the course of the disease, and any intervention would probably have to be life long to maintain remission. Secondly, many of the agents used are non-specific and have appreciable side effects. This is particularly true of cyclosporin, which ironically is toxic to 1 cells. Ethically, therefore, routine broad spectrum immunosuppression is unacceptable when used for a disease where life expectancy is considerable with conventional insulin treatment, albeit with the risk of developing complications of diabetes. Interventions should therefore be non-toxic and made at an earlier stage to be acceptable and effective-that is, before most [ cells have been destroyed. The Barts-Windsor study showed that non-diabetic siblings ofpatients with insulin dependent diabetes mellitus developed islet cell antibodies many years before the development of clinical diabetes.f With high antibody titres the risk of developing diabetes was about 50%. More recently, a series of other autoantibodies have been discovered, including insulin autoantibodies, antibodies to glutamic acid decarboxylase, and islet cell 69 kDa antibodies.67 The presence of two or more of these antibodies increases the risk of developing insulin dependent diabetes mellitus to up to 900/o-a level that makes intervention worth while. In addition, the measurement of first phase insulin secretion (the pulse of insulin that is secreted in the first few minutes after a glucose stimulus) gives a sensitive marker and predictor of the rate of progression to diabetes. This seems an ideal setting in which to test preventive LONDON, SATURDAY 4 DECEMBER 1993