An international team of scientists, led from Karolinska Institutet in Sweden, has discovered an entirely new approach to the treatment of type II diabetes. The therapy involves the blockade of signalling by a protein known as VEGF-B and this prevents fat from accumulating in the 'wrong' places, such as in muscles and in the heart. As a result the cells within these tissues are once again able to respond to insulin.
In experiments on mice and rats, the scientists have managed to both prevent the development of type II diabetes and reverse the progression of established disease. The study is published in the journal Nature, where it is described as a breakthrough in diabetes research. The findings are the result of a joint effort by Karolinska Institutet, the Ludwig Institute for Cancer Research and the Australian biopharmaceutical company CSL Limited, amongst others.
"It's a great feeling to present these results," says Professor Ulf Eriksson of the Department of Medical Biochemistry and Biophysics at Karolinska Institutet. "We discovered VEGF-B back in 1995, and since then the VEGF-B project has been a lengthy sojourn in the wilderness, but now we're making one important discovery after the other. In this present study we've shown that VEGF-B inhibition can be used to prevent and treat type II diabetes, and that this can be done with a drug candidate."
Type II diabetes is normally preceded by insulin resistance caused by obesity. When this happens, the cells no longer respond sufficiently to insulin, which leads to elevated levels of blood sugar. Insulin resistance is related to the storage of fat in the 'wrong' places, such as the muscles, blood vessels and heart, although exactly how this relationship works is not fully known.
What scientists do know, however, is that the VEGF-B protein affects the transport and storage of fat in body tissue. This was discovered by Professor Ulf Eriksson's research group in a study published in Nature in 2010. These theories have now been developed for a new study in which VEGF-B signalling was blocked in a group of diabetic mice and rats.
A total of four related studies are reported in the Nature paper. In one case, mice bred to spontaneously develop diabetes were given a drug candidate called 2H10, which is an antibody that blocks the effect of VEGF-B. The mice subsequently developed neither insulin resistance, nor diabetes. The team also crossed the diabetes strain of mice with one that lacked the ability to produce VEGF-B, and found that the offspring were protected from developing the disease.
In another two studies, the scientists took normal mice and rats that had not been specially bread to develop type II diabetes, and left them to develop the disease as a result of a fat-rich diet and the resulting obesity. In these cases, progression of the established disease was halted and reversed to varying degrees after treatment with 2H10.
"The results we present in this study represent a major breakthrough and an entirely new principle for the prevention and treatment of type II diabetes," says Professor Åke Sjöholm, consultant in diabetology at Stockholm South General Hospital. "Existing treatments can cause many adverse reactions and their effects normally wear off. There is a desperate need for new treatment strategies for type II diabetes."
Current treatments for type II diabetes normally involve initial dietary measures and/or pills designed to boost insulin secretion and sensitivity or to reduce glucose production. After a few years, such treatments eventually prove inadequate for up to 30 per cent of patients, who then require insulin injections. Type II diabetes is reaching epidemic proportions, and according to the World Health Organisation, is expected to afflict over half a billion people by 2030.
The drug candidate used in the study, 2H10, is a monoclonal antibody and is being developed by the biopharmaceutical company CSL Limited. Scientists from CSL contributed to the work and the company co-funded the study. Funding was also supplied by the Ludwig Institute for Cancer Research, the Frans Wilhelm and Waldemar von Frenckell Fund, the Wilhelm and Else Stockmann Foundation, the Novo Nordisk Foundation, the Swedish Cancer Society, the Swedish Research Council, the Torsten and Ragnar Söderberg Foundations, the Research Foundation of the Swedish Diabetes Association (Diabetesfonden), the Peter Wallenberg Foundation for Economics and Technology, and the Swedish Heart-Lung Foundation.
Earlier this year, Professor Eriksson was awarded the Heart-Lung Foundation's grand research grant of SEK 15 million (about € 1.7 million / $ 2.3 million) the largest in Sweden in the field of cardiovascular disease. The grant will be used to finance further research into VEGF-B.
- Carolina E. Hagberg, Annika Mehlem, Annelie Falkevall, Lars Muhl, Barbara C. Fam, Henrik Ortsäter, Pierre Scotney, Daniel Nyqvist, Erik Samén, Li Lu, Sharon Stone-Elander, Joseph Proietto, Sofianos Andrikopoulos, Åke Sjöholm, Andrew Nash, Ulf Eriksson. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes. Nature, 2012; DOI: 10.1038/nature11464
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