Research in genetic and molecular mechanisms of Type 1 and Type 2 diabetes
Professor and chief physician Thomas Mandrup-Poulsen, MD, DMSc, and senior researcher Nils Billestrup, PhD, head the research group constituted by 15 group members (academics, laboratory technicians and a secretary).
Overview of the group’s work
The work of the research group aims towards elucidating the molecular mechanisms underlying beta-cell failure causing Type and Type 2 diabetes using cellular and molecular biology, genetics and clinical trials as tools. Type 1 diabetes results from the destruction of the insulin-producing beta cells of the pancreas due to an inflammatory reaction in the islets of Langerhans. Treating type 1 diabetes requires daily insulin injections; the disease is related to increased morbidity and mortality.
The incidence of type 1 diabetes in Denmark is increasing at a rate of approximately 3-4% per year. There is a rapid increase in incidence in certain areas of Central Europe and in the developing countries; the global incidence is expected to double by 2030. Today, there is no cure for type 1 diabetes. Transplantation of insulin-producing cells is being tested, but islet cell rejection still occurs, despite immuno-suppressive treatment. This has prompted the group to work towards developing forms of treatment that can prevent the development of type 1 diabetes and the destruction of transplanted beta cells.
Type 2 diabetes occurs when insulin secretion cannot compensate for insulin resistance most often caused by obesity. It is now clear that beta-cell destruction accompanies Type 2 diabetes and is the main cause of progressive beta-cell failure in this disorder. Elevated glucose may cause beta-cell destruction by converging on the same pathways caused by inflammatory mediators in Type 1 diabetes.
Thus, the group is seeking to map the basic molecular processes that lead to the destruction of insulin-producing cells in Type 1 and 2 diabetes.
”A programmed death process”
When the beta cells are affected by cytokines, signal transmitters in the immune system, they start a programmed self-destruction process. If it is possible to find out exactly why and how this process begins, it might be possible to find drugs that can prevent it.
Treatment with insulin to replace the function of the damaged insulin-producing beta cells in people with type 1 and in many patients with Type 2 diabetes has been used for more than 75 years. And although the treatment has improved significantly, many patients still experience serious late and acute complications. Although beta-cell mass can be substituted by transplanting insulin-producing cells, such grafted cells are destroyed by inflammatory processes within the first years after transplantation. A breakthrough is needed in research into rescuing beta-cells in Type 1 and Type 2 diabetes.
This is why Thomas Mandrup-Poulsen’s research group is working on mapping out what happens when the beta cells of the pancreatic islets are destroyed. The group has already shown that cytokines produced by cells from the body’s own immune system harm the insulin-producing beta cells. Recently, cytokines have been implicated as mediators of glucose induced beta-cell destruction in Type 2 diabetes.
The group’s mission is to describe the molecular mechanisms underlying beta-cell destruction and how this is genetically regulated in diabetes. The group hopes to achieve this by studying protein candidates derived from our current understanding of the diabetes with with the study of protein candidates derived from screening methods.
The group has the following aims:
1. To determine the role of mitogen-activated protein kinases with emphasis on JNK kinase in the molecular destruction mechanism
2. To explore how this destruction mechanism can be prevented by altering these signal mechanisms, with a special focus on the suppressors of cytokine signalling (SOCS) molecules, and how beta-cells can be made to regenerate and proliferate
3. To understand why beta cells are particularly sensitive to signal molecules from the immune system and especially what it is in the insulin producing cells’ development that makes them sensitive to these compounds
4. To test new treatments based on these studiesin clinical trials
The work is carried out in close collaboration with several of the other research groups at and outside the Steno Diabetes Center, in particular Flemming Pociot’s group.
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