The beta cell’s dysfunction and death

Professor and chief physician Flemming Pociot DMSc heads this group made up of 14 group members (academics, bioanalysts and a secretary).

The pathogenesis for Type 1 diabetes
Type 1 diabetes develops as a result of an unfortunate combination of genetic and environmental risk factors. Both virus infections and nutritional factors have been suggested as environmental factors, but, to date, the importance of specific environmental factors is unknown.

The group’s long-lasting focus on the beta cell
The research group has long been interested in the molecular-genetic mechanisms that lead to the destruction of the insulin-producing beta cells as a part of the pathogenesis of Type 1 diabetes. The first steps in this process involve interaction between the cells of the immune system and the beta cells in the islets. During this inflammation, ’insulitus’, proinflammatory cytokines are secreted, which are particularly toxic to the beta cells. A detailed knowledge of these processes is of the utmost importance in order to prevent or intervene in the disease process.

What happens in the beta cell when it is exposed to cytokine influence?
By studying which genes and proteins are activated in the beta cell, information about the pathogenetic processes can be obtained. In the longer term, this makes it possible to design new strategies for treatment.
Many of the pathogenetic processes are genetically controlled, which is why variations in the genes that control these processes are possible risk factors for type 1 diabetes.

The group’s mission forms the outline of its research
By combining different approaches to genetics and gene and protein expression studies, it is the aim to increase the understanding of the genetic regulation and molecular mechanisms that lead to beta cell dysfunction and diabetes.

The group is pursuing these aims by focussing on the areas listed below. The group collaborates closely with other research groups at SDC.

1) Genetic studies
The group is responsible for the European part of a large international consortium, Type 1 Diabetes Genetics Consortium (T1DGC) (www.t1dgc.org), whose purpose is to identify and collect samples from more than 4,300 T1D-families with at least two siblings with type 1 diabetes. The European network (ET1DGN) (www.et1dgn.org) is coordinated by the group at SDC and is responsible for collecting samples from more than 1,200 families (~ 5,000 persons) from more than 28 countries. The project started in 2003 and sample collection is expected to be completed during 2007. Detailed genetic examinations have already begun and will continue after all samples have been collected. The aim is to characterise the most important genes for type 1 diabetes risk.

2) Characterisation of gene and protein expression and biomarkers
By analysing the gene and protein expression patterns of beta cells exposed to cytokines, beta cells that over-express certain factors, and from human islets and lymphocytes, the group can contribute to producing a detailed picture of the processes that lead to beta cell dysfunction and diabetes.
The group has access to cutting-edge technology within proteome studies, partly through SDC and partly through external collaborations. We expect that these studies can contribute to the identification of protein patterns, which will supply detailed knowledge of both the earliest pathogenetic processes and complications. Recently, the group established the SELDI protein analysis technology, which is well suited for screening a large number of samples.

3) Can type 1 diabetes be predicted at birth?
In collaboration with Statens Serum Institut, the group has begun a study of the predictive value of genetic and immunologic markers for type 1 diabetes already at birth. In this project, the PKU cards (which are blood spot cards used for all newborns) have been used for persons in Denmark born after 1981 who have developed type 1 diabetes – a total of 2,084 persons. PKU cards have also been used for 4,168 control persons, matched for time and place of birth. The cards enable collection of amplified DNA, which makes it possible to genotype more than 10,000 markers. The same PKU cards are also examined for autoantibodies and levels of cytokines. These analyses are expected to be completed by 2006-7 and will contribute to our understanding of whether it is possible to predict type 1 diabetes already at birth.

4) Danish Society for Childhood Diabetes Biobank (DSBD)
The group is also responsible for establishing and maintaining the biobank attached to DSBD. This biobank, receives samples from all children under 16 years of age newly diagnosed with type 1 diabetes. Approximately 600 samples are received annually. Since 1 October 2005, DNA and serum/plasma from approximately 1,500 probands and more than 5,000 first-degree relatives have been registered in the biobank. These samples are available for genetic studies.