A major breakthrough for children and adolescents with the deadly type 1 diabetes occurred in the 1920s as two American scientists, Banting and Best, produced the first insulin injection, thereby saving thousands upon thousands of lives. Since then, there have been dramatic improvements in insulin therapy, and much is now known about the autoimmune disease—maybe enough to develop a vaccine. Could this represent the next major breakthrough?  

Long before the outward symptoms of diabetes appear (ie, excessive urination, thirst and weight loss), the pancreas already inflamed, destroying the insulin-producing cells. Although the one affected doesn’t feel anything at this stage, the diabetes-specific antibodies can already be detected in the blood. This is the only way to determine that the immune system is fighting something (antigens) stemming from the body’s own beta cells. Only when insulin production is hindered by at least 80%, can the body no longer adequately control the blood sugar levels—resulting in hyperglycaemia (excess sugar) and the above-mentioned symptoms. By the time the patients reach the clinic with manifest symptoms, the diabetes-specific autoantibodies, as well as the body’s own insulin production, are still detectable—albeit in very small amounts.

The remission phase
After commencement of insulin therapy, the blood sugar levels normalize. The one affected feels good, and the previously over-burdened pancreas can recover somewhat. In around one-third of children, even the initial amount of insulin can be reduced. This is known as the ‘remission phase’, or ‘honeymoon phase’: The blood sugar readings are normal, no big swings, no dangerous hypos and, if hyperglycaemia does occur, it is rapidly rectified with a small amount of insulin. This phenomenon is due to the body’s own insulin reserves. Unfortunately, this phase usually only lasts for six months until these reserves are depleted and increased doses of insulin are required.

Many recent studies, including the American Diabetes Control and Complications Trial (DCCT), have shown that a long remission phase can positively influence the short-term and long-term effects of diabetes. Patients with longer remission phases were shown to have significantly fewer hypoglycaemic episodes and an approximately 50% reduced risk of developing late complications such as kidney and eye diseases than those who experienced short remission phases or none at all.

Immunosuppression doesn’t work 
Scientists are not only trying to tailor insulin therapy as close as possible to the body’s own insulin production and secretion, but are also trying to find ways to maintain the remission phase for as long as possible. In the 1980s, medical immunosuppression was attempted, in order to hinder the autoimmune process of type 1 diabetes. It occasionally worked, to a certain extent, and occasionally not. There were also side effects such as kidney damage due to the use of cyclosporine. Also, the risk of developing serious infections was very high, due to the overall immunosuppression.

Nowadays, we not only know more about the intricacies of the immune system and its effect on the body’s own organs, but we have more sophisticated medications which can control the immune system without the negative side effects. Animal and human experiments are giving hope that, eventually, such possibilities can be used in conjunction with insulin therapy so that, on diagnosis, the body’s own production of insulin can be maintained thereafter for as long as possible.

Studies about to commence
Two new studies are about to commence to examine the effects and safety of new medications in children and adolescents with newly diagnosed type 1 diabetes. 
Teplizumab (rh0KT31γ, Macrogenics Inc, USA) is an artificially produced substance that blocks the receptors on the surface of immunologically active cells, thereby re-programming the immune system. The aim is to prevent the immune system from turning against the body’s own organs. This should serve to prevent or even to stop the inflammatory process of the pancreatic beta cells. This medication has already been administered to patients with newly diagnosed type 1 diabetes, with very promising results.

The American Food and Drug Administration (FDA) have approved an international study that should, once and for all, examine whether Teplizumab is indeed effective in maintaining the body’s own insulin production for at least a year after diagnosis. This study will involve 500 children up to 10 years of age, and adolescents and young adults up to 35 years, with newly diagnosed type 1 diabetes (up to three months previous). The participants must still have remnants of insulin production. They will be randomized into four groups and, under standard study conditions, will be given the medication in three different doses. One group will receive a placebo. The medication will be injected once a day for three weeks. This process will be repeated after six months. As some side effects are expected as the body adapts to the medication, the participants will be hospitalized for a few hours after injection for observation.

Deceiving the Immune System with Diamyd™
Another way of deceiving the immune system of patients with type 1 diabetes is to administer the artificially produced molecule, rhGAD65. This molecule exists in the body and is a well known antigen associated with the development of diabetes. This substance (Diamyd™, Diamyd Therapeutics AB, Sweden) is injected subcutaneously. Already over 75 type 1 diabetic children and adolescents in Scandinavia have received it without problem. In January 2008, Professor Johnny Ludvigsson (Linkøping, Sweden), the father of this intervention strategy, presented his findings for the first time on the international arena in Hannover at the Karl-Stolte-Symposium for Paediatric Endocrinology and Diabetology.

According to Ludvigsson, his ‘vaccinated’ children demonstrated an increased insulin production up to 30 months after injection compared to placebo. Now an international study is going to take place on young patients with newly diagnosed type 1 diabetes (up to three months previous), with a positive GAD antigen result, as well as remnants of insulin production. As in the Teplizumab, the participants will be randomized to receive either the drug or placebo. The participants will be treated as outpatients, whose ability to produce insulin will be periodically observed. 

Summary
Diabetes develops when the immune system destroys the insulin-producing beta cells. In a brief remission phase, the body is still able to produce enough insulin to keep sugar levels relatively normal. Researchers are working at extending this remission phase. To this end, two studies are in the making: one on Teplizumab, and one on Diamyd™. Teplizumab re-programmes the immune system, preventing it from attacking beta cells, and Diamyd™should help maintain the body’s own insulin production also by deception of the immune system. Will these developments represent a new breakthrough in diabetes therapy? The outlook seems promising. The scientific discoveries in immunology and new developments in bioengineering, combined with the professionalism and experience applied to the carrying out of large studies, will give us the chance to answer this question.


Contact:
Prof. Olga Kordonouri, MD
Paediatric Diabetologist
Kinderkrankenhaus auf der Bult
Hannover
E-Mail: kordonouri@hka.de