YOUNG RESEARCHERS. The diabetes research at the University of Gothenburg has now been strengthened with the physician Anders Rosengren, who has been recruited to join the Wallenberg Centre for Molecular and Translational Medicine. Anders Rosengren’s research is already well on the way to identifying new treatments for type-2 diabetes.
Diabetes is the fastest growing chronic disease in the world. It is a metabolism disease where the basic problem is that the body does not form enough insulin, or that the insulin does not have enough of an effect.
“On the surface, it may seem simple, we eat wrong, we exercise too little and our blood sugar is too high. We know that the sensitivity to insulin decreases, and the function of the beta cells that produce insulin fails, but the molecular disease mechanisms behind diabetes are actually unknown in many respects,” says Anders Rosengren.
His interest in research was incited as early as his medical studies in Lund, and he earned his doctorate after graduation. His thesis was about fundamental cell physiological mechanisms in type-2 diabetes. After his doctoral defense and general residency, he did his post-doc in Seattle where he learned to work with bioinformatic methods.
Since this past autumn, he has been employed as a researcher at the Department of Metabolic Physiology at Sahlgrenska Academy, supported by Wallenberg Centre for Molecular and Translational Medicine.
“I’ve been received with great enthusiasm, and it’s very inspiring to be here,” says Anders Rosengren and confirms that the diabetes research in Gothenburg is strong:
“It’s an attractive and interesting environment, and there are good possibilities of creating synergies between different groups here. In new collaborations here, I’ll build further on what I have done to-date, although on a larger scale.”
He is passionate about translational research and taking new approaches to studying type-2 diabetes, with the ambition of being able to take results from basic research to clinical application.
Network analysis reveals groups of genes
Genetic research is often based on diseases that depend on changes in one single gene, but thanks to technical development, the genetics behind more complex diseases can now also be studied. By using network analysis, Anders Rosengren and his colleagues have found clusters of genes that are of significance to the development of diabetes, and they have also been able to identify two disease genes for type-2 diabetes that were previously unknown.
“Genetics can be compared to a landscape that makes the patients more or less sensitive to their lifestyle. It becomes increasingly clear that a more nuanced view of how genetics and the environment interact is needed to really understand type-2 diabetes.”
A smaller group of genes that the research team could identify proved to be of significance to the differentiation of the beta cells, in other words their maturation from stem cells to specialized cells.
“This evoked an exciting hypothesis: could it be that the beta cells revert in their development as a cause of their deteriorating insulin secretion in diabetes?,” Anders Rosengren asks himself.
Through network analysis, the research team was able to identify key genes that are downregulated when type-2 diabetes arises. One of the genes, SOX5, is involved in cartilage formation and also in the chromatin structure, which among other things affects what genes are expressed in different cell types and are thereby important for cell differentiation.
The defect in SOX5 leads to the beta cells having fewer calcium channels, which means that there are also fewer channels available for the release of insulin.
“We conducted a series experiments where we turned off SOX5, which led to reduced insulin secretion and decreased expression of different key genes that control the maturation state of the beta-cells.”
Several new treatments under way
He confirms that the team is on solid ground when they claim that the SOX5 gene markedly affects insulin release. By turning the gene off and on, a signature is created that exactly follows the pattern that is seen in type-2 diabetes. The discovery is well on the way to providing a potentially new approach for type-2 diabetes:
“We found a drug that has been used for several different diseases for many years, which in fact increased the expression of SOX5. We’ve seen that the drug improves the release of insulin in animal experiments, and we’ve also added the drug to beta-cells from diabetic patients and seen a doubled insulin release,” says Anders Rosengren.
For patients who have a low genetic risk of getting diabetes, the expression of SOX5 does not appear to play any role, but for those who have a high genetic risk, the SOX5 expression has an impact.
The other gene that the research team identified is ADRA2A, a gene that is defective among as many as 40 percent of everyone with diabetes. This gene codes for a receptor for adrenaline and accordingly increases the effect of adrenaline on the insulin producing cells. Adrenaline inhibits, among other things, the process inside the beta cell that leads to insulin coming out in the blood stream. The defect in the ADRA2A gene thereby becomes a constant brake on the entire insulin production, but if these receptors are blocked, the release of insulin functions again.
“We conducted a clinical study with 50 patients, who received placebo or yohimbine, a blocker of ADRA2A. We could see that yohimbine restored the defective insulin release in those who received the medication,” says Anders about the results published in Science Translational Medicine 2014:
“The study received attention since it was the first time it was possible to affect a disease mechanism for diabetes based on a risk gene.”
However, yohimbine must be modified to be able to become a good candidate drug for type-2 diabetes since the current molecule also increases blood pressure. The research team is now working on changing the molecule so that it does not pass through the blood-brain barrier.
From network analysis – to broccoli
Many patients with type-2 diabetes have higher blood sugar levels at night, known as fasting glucose. Many diabetics take the drug metformin to balance their glucose levels over the day, but the substance affects the stomach and cannot be given to those with kidney failure, which is common in type-2 diabetes. Through a network analysis of the liver’s genes, the group has been able to create a picture of the organ’s disease signature and was able to show what genes changed their expression in people with diabetes.
“We’ve found a substance that can reverse the signature we see in the liver, and can restore the pattern of gene expression. The substance has thus far been studied as a treatment for cancer and inflammatory diseases, but not for diabetes,” says Anders.
Just like metformin, the substance inhibits the liver’s glucose production, but the functional mechanism is entirely different. The substance exists naturally at high amounts in broccoli. Through collaboration with Lantmännen, they were able to develop a broccoli extract where every daily dose is the equivalent of four or five kilograms of broccoli.
“We recently concluded a clinical study with very promising results, which we will also publish soon. It’s an interesting potential treatment, since the broccoli extract is more functional food than traditional medicine,” says Anders.
Raising both quality of life and blood sugar
Another ambition for Anders Rosengren is to be able to take a holistic approach to the treatment of patients with type-2 diabetes by integrating pharmaceutical treatment with lifestyle changes. Here, there is great potential through the development in e-health, in his opinion:
“The Internet is a fantastic platform, and there are already many commercial players that provide various health tools. We want to create a patient-centric tool that has a scientific foundation and helps patients to make long-term changes in lifestyle.”
The e-health project that he and his colleagues are working on involves a new tool that will both be used for treatment and research. This is a program that patients can use from home on their computer or mobile phone, which gives them different tools to make individually adapted lifestyle changes, and also measures both the biological and psychological effect of the lifestyle changes.
“Diabetes is often seen as an isolated part of the patient’s life, but it is important to consider the patient’s entire situation to obtain sustainable solutions. We learn a great deal about the disease through the project, and how we can conduct lifestyle interventions,” says Anders Rosengren, whose project is now being run from the University of Gothenburg:
“We recruit patients throughout the country, and investigate how the tool can affect both blood sugar and quality of life. We have great hopes that the tool will have an impact in the healthcare services, through the academic seriousness that is behind it in contrast to the majority of e-health solutions that exist today for lifestyle diseases.”
TEXT: ELIN LINDSTRÖM CLAESSEN
PHOTO: JOHAN WINGBORG/GU
About the Wallenberg Centre for Molecular and Translational Medicine
- The Wallenberg Centre for Molecular and Translational Medicine (WCMTM) is a part of a national endeavor to strengthen Sweden’s position as a world-leading nation in the life sciences.
- Together with the University of Gothenburg, AstraZeneca and the Västra Götaland Region, the Knut and Alice Wallenberg Foundation is investing at least SEK 620 million over a ten-year period. Similar centers are being built up at the same time in Lund, Umeå and Linköping.
- The recruitment of internationally promising researchers in molecular medicine is one of WCMTM’s primary missions and the majority of researchers will be employed at WCMTM in the next few years with their home base at the various institutes of Sahlgrenska Academy and the Faculty of Science to build up their research teams.
- Significant effort is being devoted to linking the WCMTM researchers to hospital environments and AstraZeneca to create strong translational environments.
- WCMTM also supports specific translational projects and infrastructures that bridge research and clinical practice to secure the breadth in WCMTM.