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Cause of type 2 diabetes identified

The skeletal system controls the development of the metabolic disorder

Conducting a long-term study on the development of diabetes mellitus type 2, a team of researchers led by Prof. Dr. Georg Schett, Director of the Department of Internal Medicine 3 at the University Hospital of Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), has now discovered what causes insulin resistance. The results published in ‘Nature Medicine’ show that the RANKL protein contributes significantly to the development of insulin resistance in the liver. Interestingly, RANKL is normally known to play a role in the skeletal system, where it is essential to bone resorption. The new insights promise new prevention and treatment approaches for the disorder that can quickly be translated into clinical practice.

Diabetes mellitus is a metabolic disorder that leads to hyperglycaemia. The difference to adolescent insulin deficiency diabetes is that in adult onset type 2 diabetes, the body grows resistant to the blood sugar-lowering hormone insulin. The pancreas does excrete an excess of insulin in patients with adult onset diabetes, but the hormone loses its hypoglycaemic effect on the organs. This is known as insulin resistance. In the long-term, elevated blood sugar levels damage blood vessels and nerves. Among the secondary diseases are heart attacks, strokes, renal insufficiency and damage to the retina.

The concentration of the RANKL protein in the blood of over 1000 patients was measured over the course of the long-term study. ‘This research showed that persons with high RANKL levels had, a significantly higher risk of developing diabetes mellitus type 2, irrespective of sex and age,’ Prof. Dr. Schett summarises. The Bruneck Study was a 20-year observation of healthy inhabitants of the town of Bruneck in South Tyrol. Its goal was to research the causes of heart attacks, strokes, diabetes, osteoporosis and diseases of the nervous system. The study was initiated by Professor Johann Willeit and Professor Stefan Kiechl from Innsbruck Medical University as well as Professor Siegfried Oberhollenzer from Bruneck Hospital.

The mechanisms and ways in which RANKL leads to insulin resistance and diabetes were discovered over the course of several years of laboratory research, conducted by FAU’s Professor Stefan Wirtz of the Department of Internal Medicine 1 (Director: Prof. Markus Neurath) and Dr. Jürgen Wittmann of the Division of Molecular Immunology at the Department of Internal Medicine 3 (Head: Prof. Dr. Hans Martin Jäck) together with Professor Herbert Tilg of Innsbruck Medical University. The researchers inhibited the activation of RANKL in the liver, thus achieving a normalisation of blood sugar levels. ‘The laboratory examinations confirm that the RANKL protein, which is actually responsible for the development of osteoporosis, also plays a central role in the development of diabetes,’ Prof. Schett says. This shows that our skeletal system has a significant influence on blood sugar metabolism and that the two organs closely communicate with each other.

It was recently found that the widely used diabetes drug Metformin influences RANKL activity. Researchers are now faced with the task of developing and testing specific diabetes medications against RANKL. Inhibition of RANKL is already successfully used to treat osteoporosis, which provides a head start in the development of a new treatment for diabetes. ‘This fact could allow us to realise RANKL inhibition as a way of preventing and treating type 2 diabetes mellitus within only a few years,’ the researchers state confidently.

Further information:

Prof. Dr. Georg Schett
Phone: +49 (0)9131 85 -39133 or -39131
georg.schett@uk-erlangen.de

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