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Médecine et santé

The diabetes genes

 
 
image
Back of the eye of a diabetic patient. The head of the optic nerve is visible (bright spot) as are some haemorrhages (irregular spots).
© INSERM

What part is played by genetic determinism in diabetes? To understand its role in this complex disease, a consortium of European laboratories has assembled medical data from several thousands of families of patients and defined a common approach based on post-genomic analysis. Given that, in Europe, 8% of health care expenditure is attributable to diabetes and its serious complications such as blindness, kidney problems, and cardiovascular problems, the issue is a crucial one. This research is opening the way to producing new medicines and is inaugurating an experimental approach applicable to other diseases.

     

There are two types of diabetes. The first (type 1), affecting approximately 10% of diabetics, strikes young people and is accompanied by the progressive destruction of the pancreas. The second (type 2) is a disease with onset in adulthood and is associated with a loss of sensitivity to the hormones secreted by the pancreas, i.e. insulin. More than 100 million people in the world are affected by this disease, the incidence of which increases with age. The researchers of two successive European projects have been tackling the second type of diabetes of since 1996.

Genetic determinism

At the beginning of the 1990s, the team of French geneticist Philippe Froguel of the Institut Pasteur of Lille showed that a familial sub-form of type 2 diabetes could be caused by mutations in genes coding for an enzyme, glucokinase, and for a transcription factor, hepatocyte nuclear factor. These genes do not however cause the disease, in the large majority of cases, but predispose certain individuals to it in interaction with other risk factors (age, nutrition, weight, lack of physical activity). How could one then distinguish the part played by genetic influence and specify which genes were involved?

The goal of the first research project supported by the Union was to gather data on patients and their families, compiling different types of information (DNA samples, data concerning lifestyle and eating habits) which would constitute one of the most important data bases in the world. Since 1999 this research has been pursued through the GIFT European network within the framework of the programme Quality of life and management of living resources.

"The only way to understand the role of genetic determinism in such a complex disease is to combine traditional genetic studies with the post-genomic approach. This term, which is formed by contracting the words genetics and informatics, denotes the new horizon of biomedical research which seeks to comprehend and interpret the enormous quantities of information we have obtained on the human genome sequence", explains Philippe Froguel, coordinator of the network.

The Danish partner in GIFT is responsible for genetic epidemiology research aimed at identifying the genes which predispose an individual to diabetes, their position on the chromosomes and their sequences. A task of this kind requires expertise in bio-informatics and in statistical analysis, which is the contribution of the British team. Considerable progress has been made with this first part of the research, in particular with the identification of a DNA sequence (a locus) significant for predisposition to type 2 diabetes on chromosome 20. But while it is one thing to know which genes are involved in predisposition, it is another to know their level of expression in normal or pathological conditions, namely their level of transcription into RNA which, in turn, will be translated into protein.

The post-genomic approach

This is where the post-genomic approach comes into play. One of GIFT's goals is to apply the cutting edge technology of this innovatory discipline to the study of diabetes by using DNA chips to study the level of expression of genes which predispose humans to diabetes, but also in animal models of diabetes. Short oligonucleotides which are specific to the genes predisposing to diabetes and originating, for example, from the preparation of RNA from a diabetic patient, are placed and fixed on to the surface of a "diabetic chip". When the chip is placed in contact with a sample of DNA to be analysed, the nucleic acids which it contains and which correspond to the expression of the targeted predisposition genes will hybridise (that is to say they will form a double-strand molecule) with the primers fixed on the chip. This hybridisation releases an optical signal which is subsequently analysed automatically.

Molecular routes to new medicines

The study of predisposition genes could have important repercussions for pharmaceutical research. A knowledge of the levels of expression of genes involved in a predisposition to diabetes may indeed provide molecular routes leading to the conception of new medicines. If, for example, a certain gene is over-expressed in a diabetic patient, it is possible to conceive of molecules which will interact with the protein encoded by this gene in order to reduce its harmful effect. This approach, known as "from the gene to the protein" constitutes one of the most promising industrial outlooks for the post-genomic area.

"Our work on diabetes could serve as an experimental paradigm for studying other diseases which remain enigmas for biomedical research", comments Philippe Froguel. And he quotes, in no particular order, "cancer, hypertension, neurodegenerative diseases, such as Alzheimer's, or obesity".

 
Projects
- Identification of the genes involved in the pathogenesis of non-insulin-dependant diabetes mellitus (NIDMM): a paradigm for multifactorial diseases
- Genomics Integrated Force on Type 2 diabetes (GIFT)

Reference
- BMH4-CT950062
- QLG2-1999-00546

Programme
- Biomedicine
- Quality of life and management of living resources

Contact
Philippe Froguel, CNRS, Institut Pasteur de Lille (FR)
Fax: +33-3-20877229
E-mail : Philippe.Froguel@
mail-good.pasteur-lille.fr

Partners
- CNRS, Institut Pasteur, Lille, France (coordinator)
- Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Paris, France
- Université de Paris VII, France
- Steno Diabetes Centre, Gentofte, Denmark
- University of Lund, Malmö, Sweden
- The Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom

The GIFT project also involves the following partners:
- University of Exeter, Exeter, United Kingdom
- Universidad de Barcelona, Barcelona, Spain
- Imperial College of Science, Technology and Medicine, London, United Kingdom
- Novo-Nordisk A/S, Bagsvaerd, Denmark
- Université de Lausanne, Lausanne, Switzerland

image
Micro-encapsulated Islets of Langerhans - Whole pancreas transplants have been carried out for several years. Researchers are studying the feasibility of transplanting the Islets of Langerhans, which may already be perfectly isolated from the rest of the pancreas. These experiments, successfully performed on rats and dogs, have not yet been conclusive for men. The likely direction of the research is towards grafts from pigs.
© INSERM/G.Reach

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