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A multicentred approach for the treatment and prevention of diabetes

In order to counteract the increase in the number of diabetics, it is necessary to take into account the entire psychosocial environment of the patients, states Prof. Dr. Peter Nawroth, a physician from Heidelberg University Hospital. The prevention of late complications must be a major goal of any treatment and patient consultation. By focusing on the development and investigation of the RAGE-dependent reaction system, Nawroth and his team have succeeded in significantly driving forward the understanding of the molecular relationships of late diabetes-related damage.

The frequency of diabetes is increasing rapidly worldwide. The German Diabetes Health Report 2008 estimates that in Germany alone, the number of people suffering from diabetes type 2 is greater than 10 million. The Report also calls Germany a “diabetes country”. Previously, diabetes type 2, which accounts for about 95 percent of all diabetes cases, was regarded as a typical old-age disease. Nowadays, it is diagnosed more frequently in younger people, particularly children and adolescents who are extremely overweight.

Taking into account psychosocial factors

Prof. Dr. Peter Nawroth © University of Heidelberg

In his speech opening the Annual Meeting of the German Diabetes Society (DDG) 2007, Professor Dr. Peter Nawroth, who was the then president of the meeting, explained, "Lifestyle intervention studies have shown that the reduction of body weight by a few kilograms, daily exercise for thirty minutes and healthy nutrition are sufficient to flatten the steep curve of new diabetes type 2 cases. Despite all health policy efforts, it is difficult to put such lifestyle changes into action - while education and secure psychosocial status are positive indicators for the success of such measures, depression, unemployment and social isolation are factors that undo all preventive measures." Nawroth concludes that good advice is not sufficient to bring the problem under control; people need to be seen in their complete psychosocial environment.

A study dealing with "Diabetes and Migrants" focuses on these relationships. The study will be presented at this year's DDG meeting to be held in Leipzig between 20th and 23rd May. The study finds that around one million migrants in Germany suffer from diabetes, but it also finds that only 15 percent of the migrants actually know what diabetes is. Due to the fact that so many people are unaware of the risks and symptoms of the disease, diabetes self-management seems impossible and the risk of  sufferers contracting secondary diseases is very high.

The prevention of late damage as a result of diabetes must be a major goal of diabetes treatment and prevention. Diabetes is one of the most important risk factors for cardiac infarction and stroke, and is the most frequent cause of blindness and terminal kidney failure.

Diabetic foot

A particular problem is the diabetic foot syndrome, which affects one in five patients with long-term diabetes. Often unnoticed by the sufferers themselves, abscesses develop that do not heal without appropriate treatment therefore leading to necrosis, which requires the amputation of feet or toes. In Germany, amputations are necessary in as many as 40,000 patients suffering from diabetic foot syndrome. In many cases this can be prevented. “The earlier people come to see us, the greater the chance that they will be able to walk again without any problems,” explained Nawroth. In the interdisciplinary diabetes outpatient clinic at the University of Heidelberg, diabetes and vascular medicine experts are working with vascular surgeons, orthopaedists and plastic surgeons in order to do everything they can to save the feet of diabetic patients suffering from open wounds and infections, thus enabling them to walk again. Pedicurists and orthopaedic shoemakers take care to prevent pressure points and injuries.

Diabetes outpatient clinic at the University Hospital of Heidelberg © University Hospital Heidelberg

With its diabetes outpatient clinic, Heidelberg is the first University Hospital in Germany to take part in the "Curaplan" programme of the AOK (statutory health insurance company in Germany). GPs and their patients agree on a treatment regime that involves the long-term treatment of diabetes, including the regular monitoring of blood pressure and blood glucose levels. This contributes to helping patients whose disease is difficult to control or those who suffer from complications such as foot abscesses, explains Nawroth.

RAGE and diabetes

Working with scientists at the German Cancer Research Centre in Heidelberg and Columbia University in New York, Nawroth and his team have discovered a molecule that is key to the development of late damage in diabetics. This molecule, known as RAGE, is a receptor for “advanced glycation end products” (AGE). This is a multi-ligand receptor that is a member of the immunoglobulin superfamily.

Glycation is the non-enzymatic binding of sugar molecules to proteins or lipids, for example. “In diabetes patients, the glycation of haemoglobin has for many years now been an excellent measure of treatment success,” said Nawroth. The better the blood glucose level can be adjusted, the lower the HbA1c value, which reflects the degree of haemoglobin glycation.” Glycation leads to AGE molecules that are bound by RAGE and induce a reaction cascade inside the cell. This cascade involves activated oxygen molecules, the activation of kinases that transfer phosphate groups to other molecules as well as certain transcription factors. The transcription factor NF-kappaB, which provides for the production of proteins that induce and maintain inflammatory and defence reactions in the body, plays an important role in this process.

Mice were given RAGE molecules that subsequently circulated in the animals’ blood and caught AGE and other substances that would otherwise be bound to the cell membrane-bound RAGE receptor and induce reaction cascades. The researchers found that soluble RAGE molecules improved the health of mice suffering from diabetes, vascular calcification, Alzheimer’s and chronic inflammation. Knock-out mice that lacked the RAGE gene provided the researchers with the necessary evidence for the importance of RAGE: these mice also contracted diabetes, but developed less damage to blood vessels and nerves.

Dr. Angelika Bierhaus © University Hospital Heidelberg

In humans it was possible to show that the NF-kappaB factor in the blood cells of diabetics and patients with chronic colon inflammation is permanently active. Another indication that RAGE has a similar role in humans and mice, stems from a group of people who have inherited a defective RAGE gene. These people are protected against diabetes-related late damage of the kidneys, just like the knock-out mice described above.

Long-term diabetics gradually lose the sensation of pain; they are no longer able to sense minor injuries, which then leads to inflammation and abscesses. Dr. Angelika Bierhaus and her team in Prof. Nawroth's department have been able to show that RAGE also plays a decisive role in diabetes patients suffering from diabetic neuropathy. The nerve cells of diabetes patients with neuropathy, the quantity of RAGE and activated NF-kappaB is far higher than normal. Nawroth and his team were able to provide further evidence on the importance of this reaction pathway in the development of neuropathy. This opens up new strategies for the treatment of patients with chronic nerve inflammation, for which few therapies are available.

Diabetology is just in its infancy

The scientists in Heidelberg have also been able to show that RAGE not only plays a role in diabetics, inflammation and degradation processes, but also in sepsis as well as acting as a “danger sensor ” and modulating behaviour such as fear reactions. The in-depth investigation of individual aspects of a complex systemic disease such as diabetes mellitus, often leads to new, sometimes surprising findings whose consequences go far beyond the initial research goal. In the talk given at the 42nd DDG meeting, Nawroth said that these findings open up new approaches that may lead to new alternative therapies, further insights in patient treatment and nutrition research, in the therapy of high blood pressure and kidneys, cardiology and angiology as well as psychosocial disciplines. The meeting focused on the motto “Diabetes has only just begun.”

Further information:
Prof. Dr. med. Peter Paul Nawroth
Medical Director
Internal Medicine I and Clinical Chemistry
University Hospital Heidelberg
Im Neuenheimer Feld 410
69120 Heidelberg
Tel.: +49 (0)6221-56 8600
Fax: +49 (0)6221-56 5226

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/a-multicentred-approach-for-the-treatment-and-prevention-of-diabetes