Safer treatment for diabetes

It sounds like a miracle cure. Injecting the hormone FGF1 into mice with type 2 diabetes appears to stabilize the blood glucose level for days on end, without side effects. Last summer, Hans Jonker, Associate Professor in the Faculty of Medicine/UMCG, published a second article in Nature about this discovery. In the alumni magazine Broerstraat 5, Hans Jonker tells about his research.

Text: René Fransen

Diabetes is a growing problem. Type 2 diabetes (also known as adult-onset diabetes) is becoming increasingly common. The disease develops as the body loses its sensitivity to the hormone insulin, which is needed to regulate the amount of sugar (glucose) in the blood. Too much sugar in the blood harms the body in the long-term, but if someone with diabetes has too little sugar in the blood, they can develop a ‘hypo’ and lose consciousness. Drugs known as TZDs can be used to increase the body’s sensitivity to insulin. ‘But TZDs have undesirable side effects, such as oedema, osteoporosis and even heart failure,’ explains Hans Jonker. ‘Injecting insulin is obviously a possibility, but too high a dose can cause a hypo.’

Stumbled upon

Jonker is Associate Professor in the Department of Paediatrics of the Faculty of Medicine and the UMCG. He is currently trying to find a safe alternative for diabetes patients via a research line he stumbled upon seven years ago. ‘I was working as a postdoc researcher in the Salk Institute for Biological Studies in the United States,’ he explains. ‘I had developed a technique for studying the factors controlling whether certain genes are switched on or off, including the gene responsible for producing the hormone FGF1. We already knew that this hormone stimulated cell growth in cell cultures, but we didn’t know what it did in the body.’ Jonker’s research showed that FGF1 is activated by a protein called PPARγ. ‘This protein just happened to be the connecting point for the TZD drugs used to treat type 2 diabetes. So – without actually looking for it – we had stumbled upon a link between FGF1 and diabetes.’

Obesity

Jonker continued studying the connection between FGF1 and diabetes. He set up a research project using mice that were no longer able to produce FGF1. The hormone FGF1 turned out to regulate the way that fat tissue adapts during periods when too much or too little food is consumed. ‘When we fed the animals a fatty diet, they developed type 2 diabetes faster than normal. And they were unable to store and use fats, particularly abdominal fat.’ Abdominal fat is an important risk factor in the development of diabetes in humans, and FGF1 therefore plays a crucial role.

As a result of this discovery, Jonker published an article in Nature in 2012. He had been working in the UMCG for two years at this point. This summer, he published the results of a follow-up study, again in Nature. ‘The purport of the first publication was fundamental, and largely of interest to researchers. But the second one may be very important to patients.’

Spectacular

For the new study, the researchers injected FGF1 into mice with type 2 diabetes. The results were nothing short of spectacular: ‘The blood glucose levels remained normal for a staggering three days. This was an amazing result; the effect of injecting insulin disappears much more quickly. What’s more, previous research had shown that FGF1 disappears from the blood in no time, so we really didn’t expect it to work for this long. It possibly bonds with a target outside the bloodstream, enabling it stay active for a while longer.’

In addition, an injection with FGF1 does not seem to cause a dangerous drop in the blood glucose level, as is the case with insulin if a patient is not careful about administering the right dose. ‘Even high doses of FGF1 don’t cause a hypo,’ says Jonker. Furthermore, it is a hormone made by the body, which reduces the chance of side effects. ‘We treated mice for a maximum of five weeks and saw no negative side effects during this period. There were a few positive side effects; the mice became more sensitive to insulin and there was a huge drop in fat accumulating in the liver.’

However, there was one point of concern, admits Jonker. ‘FGF1 first came to light as a hormone that stimulates cell growth. This implies a long-term risk of unbridled cell growth, in other words cancer.’ But they seem to have found a solution to this problem. ‘We’ve managed to trim off a tiny piece of the protein in a way that stops it from stimulating cell growth but still enables it to have a positive effect on the blood glucose level, insulin sensitivity and the accumulation of fat in the liver.’

Too good to be true

A substance that regulates the blood glucose level without side effects or the risk of overdose. It sounds too good to be true. ‘But there’s still a big gap between promising results with mice and getting a drug onto the pharmacy shelves,’ warns Jonker. Plans to test the drug on diabetes patients are already being forged. ‘The first tests will take place in the United States. I’m still working closely with colleagues in the Salk Institute on this project.’ The top American biologist Ronald M. Evans is head of the lab where Jonker used to work. He is also co-author of the Nature publications and was this year awarded an honorary doctorate by the University of Groningen.

Clinical trials could start within two years. They will show whether FGF1 has the same effect on humans as it does on mice. ‘But even if the results are disappointing, we’ll still have come a long way. At least we now know that it’s possible to normalize the blood glucose level without causing it to drop too far.’

Researchers are still not sure exactly how FGF1 works. Jonker has a lot of unanswered questions. ‘We’ve published two articles about this hormone in Nature, but even after seven years of research, I don’t think we know very much about it,’ he laughs. There is still a lot of work to be done, and not only with regard to FGF1: ‘I started this research by devising a technique to find out how genes are controlled. FGF1 was not the only interesting result – I’ve got a whole drawer full of them!’

Curriculum Vitae

Hans Jonker (1974) studied molecular biology in Utrecht. He was awarded a PhD with distinction by the University of Amsterdam in 2003, for research carried out at the Dutch Cancer Institute. He worked as a postdoc researcher in the laboratory run by Ronald M. Evans at the Salk Institute for Biological Studies in California between 2005 and 2010. After this, he went to Groningen as a researcher in the Department of Paediatrics in the Centre for Liver, Digestive and Metabolic Diseases of the UMCG, where he led his own group conducting research into the molecular interactions between lifestyle and metabolic diseases, such as diabetes. The research focused specifically on the regulation of the genes involved in energy metabolism, with the aim of improving treatment for metabolic disorders such as obesity, diabetes and cardiovascular disease. In 2012, Jonker received a Vidi grant from the Netherlands Organisation for Scientific Research (NWO). His research is co-funded by the Diabetes Fund and the Stomach, Liver and Intestinal Foundation.