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The fondus oculis
of the diabetes subject. The head of the optical nerve is visible
(clear spot) as well as indications of bleeding (irregular spots)
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For the physiologist,
diabetes is an illness whose main symptom is the presence of sugars in the
urine. For the doctor, there is diabetes... and diabetes. This is because
the presence of sugars in the urine can be a symptom of two very different
diseases. Type 1 diabetes, which accounts for about 10% of all diabetes
patients, affects young people and causes a progressive destruction of the
pancreas. Type 2 is an illness of later life and involves a loss of sensitivity
to insulin, the hormone secreted by the pancreas. Also known as non-insulin-dependent
diabetes, type 2 diabetes affects more than 100 million people worldwide
and becomes increasingly common with age. In Europe, diabetes and its serious
complications - such as blindness, kidney complaints and cardiovascular
problems - account for 8% of all medical costs.
Genetic
determinism
In the early 1990s, a team headed by the French geneticist Philippe Froguel
of the Institut Pasteur in Lille showed that a sub-form of type 2 diabetes
could be caused by mutations of the coding genes for the enzyme glucokinase
and for the nuclear transcription factor for hepatocytes. This was the
first experimental proof of the role of genetic determinism in diabetes.
However, in the vast majority of type 2 diabetes cases the genes do not
actually cause the illness but rather predispose a particular individual
to developing it in interaction with what are known as environmental risk
factors, such as age, nutrition, weight or lack of physical activity.
To use the jargon of the experts, type 2 diabetes is a multigenic and
polyfactoral disease.
The question
therefore is how to identify the role of genetics as distinct from lifestyle,
and how to determine what genes are involved. This is the task of GIFT
(Genome Integrated Force on Type 2 diabetes), a European research network
coordinated by Philippe Froguel and financed by the EU.(1)
As in any
study of medical genetics, the first step is to gather data on patient
families. Several teams had already collected anonymous medical records
on patients suffering from type 2 diabetes, complete with DNA samples
and information on lifestyles and diet. GIFT entered these British, Danish,
French and Swedish data into a single database - one of the biggest in
the world, and one which is soon to have its own Internet site.
The post-genomic
approach
But how can such a vast amount of information be used? 'The only way to
understand the genetic determinism of such a complex disease is to combine
a traditional genetic study with a post-genomic approach. The term itself
is a contraction of 'genetic' and 'informatic', and indicates the new
horizons opening up to biomedical research, which is seeking to understand
and interpret the vast amount of information now available on the human
genome sequence,' explains Philippe Froguel.
Genes
and biochips
In a
'diabetes biochip', short oligonucleotides specific to diabetes predisposition
genes - taken from the RNA preparations of a diabetes patient, for
example - are deposited and fixed on the biochip surface. When this
comes into contact with a DNA sample to be analysed, the nucleic acids
it contains that correspond to the expression of the targeted predisposition
genes will hybridise (i.e. form a double strand molecule) with prilers
attached to the biochip. This hybridisation triggers an optical signal
which is then automatically analysed. |
GIFT's Danish
partner is responsible for the genetic epidemiological study to identify
which genes predispose an individual to developing diabetes, their position
on the chromosomes and their sequences. A British team is providing the
necessary expertise in the field of bio-informatics and statistical analysis.
This first research stage has already made considerable progress, identifying
on chromosome 20 a DNA sequence (a locus) which is significant for the
predisposition to develop type 2 diabetes. But it is one thing to identify
the genes involved in the predisposition and quite another to determine
their level of expression under normal or pathological conditions, i.e.
their level of transcription into RNA which will in turn be translated
into protein.
This is
where the post-genomic approach comes in. One of GIFT's objectives is
to apply the advanced techniques of DNA biochip or microarray technology
to the study of diabetes. This makes it possible, simultaneously and automatically,
to analyse the level of expression of several thousand genes (see box).
These diabetes biochips will be developed in cooperation with the ValiGene
biotechnology company in Paris, as part of the EU's incentive policy to
create a genuine European DNA biochips industry able to rival US supremacy.
These chips
will be used to study the level of expression of predisposition genes
both in man and in animal diabetes models. This should make it possible
to identify a number of potentially susceptible genes, the role of which
can then be tested in man.
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Micro-encapsulated
islets of Langerhans. Complete pancreas transplants have been carried
out for a number of years. Researchers are now studying the possibility
of transplanting islets of Langerhans which can already be separated
from the rest of the pancreas. Experiments have proved successful
on rats and dogs, but are not yet conclusive for man. Research is
currently concentrating on transplanting pig islets.
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Molecular
clues to developing new drugs
What results can be expected? It could be supposed that a programme based
on predisposition genes would yield results in the field of prevention,
for example identifying patients genetically likely to develop the disease
before they actually become ill. But this is not the area the GIFT researchers
are concentrating on, believing the lifestyle influence to be too great
to envisage any genetic screening. On the other hand, the study of predisposition
genes could produce significant results in the field of pharmaceutical
research. A knowledge of the levels of expression of the genes involved
in a predisposition to diabetes could provide molecular clues to developing
new drugs. If a particular gene is found to be over-expressed in a diabetes
patient, molecules could be developed to interact with the protein coded
by this gene and thereby reduce its harmful effect. This is one of the
most promising industrial applications of post-genomics.
The consortium
is currently establishing links with several European pharmaceutical groups
with a view to developing new forms of treatment based on the genes discovered.
This is why patent applications have been made for these genes. There
are also plans to launch a European start-up company specialising in diabetes
genomics. Finally, the consortium's study will make it possible to adopt
a joint approach for research on genetic predisposition in multifactoral
diseases. 'Our work on diabetes could serve as an experimental paradigm
for the study of other diseases which remain an enigma to biomedical research,'
explains Philippe Froguel, citing 'cancer, hypertension, neurodegenerative
diseases such as Alzheimer's disease, and obesity' as possible examples.
(1) GIFT received 1.94 million
euros from the EU's Biomedicine programme (FP4) and is continuing to be
funded under the new programme, Quality of life and living resources.
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