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Teaming Up Against Diabetes

Three laboratories in the French city of Lille have come together to form the European Genomic Institute for Diabetes. Their goal is to pool their approaches and resources to better prevent, predict, and treat diabetes and its complications.

It's the early afternoon on the Calmette Campus in Lille. In a small room on the second floor of a building, two technicians are busy extracting DNA from blood samples from diabetes patients. Downstairs, automated instruments are sequencing genes from the patients' cells at a furious pace. Down a hall, bioinformaticians and biostatisticians are analyzing genetic data on their computer screens.
dna sequencer

© P. Latron/INSERM

A high-throughput automated DNA sequencer is used to track gene mutations tied to T2D.

The summer sees no decrease in activity for the teams at the Genetics of Multifactorial Diseases Research Unit,1 one of the three labs that make up the new European Genomic Institute for Diabetes (EGID) launched last May. And researchers are no doubt spurred on by their recent findings. Also heading the section of Genomic Medicine at London's Imperial College, EGID Director Philippe Froguel and his colleagues were the first to draw up the genetic map not only of type 2 diabetes (T2D), but also of the severe obesity which strongly predisposes people to the disease. This type of diabetes, which is rapidly spreading, already affects 180 million people all over the world (see box). The scientists have also shown that there is a link between the disruption of the body's biological clock and the onset of T2D. And they certainly don't intend to stop there. “Our goal now is to discover the rarer DNA mutations involved in type 2 diabetes,” says Froguel. To help them achieve this, the lab has one of the best high-throughput genomic platforms in France. “This new device is technically able to sequence the entire human genome in a week,” claims an engineer. In addition, the team has one of the largest gene banks in the world. “In these cold chambers, we keep around 25,000 samples of DNA from diabetic and obese families,” he adds. “And our anonymous databases contain biological and medical information on approximately 40,000 people.” Froguel and his team are now trying to discover the epigenetic factors involved in T2D, in other words the environmental factors that affect the expression of the genes involved in the disease. “Right now, we're focusing on the study of the genome of obese patients whose T2D appears to abate considerably after a surgery that treats their obesity by connecting the stomach to a lower part of the intestine,” he explains.
DNA extraction

© P. Latron/INSERM

DNA extraction from patients' blood samples using one of the best high-throughput automated platforms in France.

Helping Froguel is surgeon François Pattou, the director of the Diabetes Biotherapy Unit,2 one of EGID's two other labs. He regularly carries out this operation on his patients at the Lille Regional University Hospital Center (CHRU). “Short-circuiting the upper part of the intestine seems to trigger overproduction of intestinal peptides that revive the secretion of insulin,” he explains. “That's why we're now beginning to offer this operation to T2D patients who are not necessarily suffering from severe obesity.” Yet this surgical treatment should only be carried out on patients suffering from the most serious forms of the disease. During the surgery, Pattou takes tissue samples which are sent to Froguel's lab for genomic analysis. The aim is to discover the genes involved in the resumption of insulin secretion.
But the biotherapy carried out in Pattou's unit goes even further. One of his teams, led by the diabetes specialist Marie-Christine Vantyghem, has recently obtained spectacular results by transplanting islets of Langerhans, clusters of pancreatic cells that produce insulin and which are defective in so-called type 1 diabetes. “Half of the fourteen transplanted patients no longer need insulin injections, even as long as five years after the transplant. This is the best result ever obtained worldwide,” adds Pattou. The key to this success lies in part in continuous technical improvements performed in the laboratory animal facility, across the courtyard. For instance, researchers there are attempting intramuscular transplants of islets of Langerhans into pigs. But success also relies on work performed before transplant. In the aseptic environment of the biotherapy platform, Julie Kerr-Conte's team has acquired an internationally recognized expertise in isolating islets of Langerhans. Currently, islets are removed from the pancreas of brain-dead donors. In the future, they may come from embryonic stem cells differentiated into pancreatic cells.
Biotherapy platform

© P. Latron/INSERM

Biotherapy platform specialized in isolating human islets of Langerhans. The researchers' expertise in this field is internationally renowned.

EGID's third laboratory, housed on two university hospital campuses,3 is headed by Bart Staels.4 His team tests drugs that may regulate the expression of the genes involved in diabetes and in the resulting cardiovascular diseases. Following the discovery of a link between the disruption of the body's biological clock and diabetes, the scientists have started studying mice whose circadian rhythm has been perturbated. They identify the genes whose expression is perturbed, and study their transcriptional regulation. The lab has great expertise in the nuclear receptors involved in the transcriptional regulation of genes, some of which are defective in diabetics. “For instance, we're trying to improve pharmacological molecules that may act on one of these receptors called PPARg,” Staels explains. He is also one of the founders of the firm Genfit, which is developing a new antidiabetic drug that acts on this type of receptor. The drug is currently being tested on a small number of patients. “Our lab is also investigating the role of macrophages–immune cells–and of bile acid in the disease. Here again, certain nuclear receptors seem to play an important role,” he adds.
Fighting the disease on multiple fronts, EGID's success lies in the genuine synergy between its different teams, all of which enjoy international recognition. “Our goal is to make the Institute one of the world leaders in diabetes research and in the fight against the disease,” explains Jean-Benoist Duburcq, CNRS regional representative and head of the EGID project. “To succeed, we'll be pulling out all the stops to attract the best foreign researchers and students, work with renowned private sector partners, and bring together French diabetes clinicians. We're also committed to high-level training and general public information.” At the end of 2012, the three teams, numbering 137 colleagues in all, will be brought together on one site, on the Lille university campus.

Jean-Philippe Braly

There are two types of diabetes. Type 1 diabetes is an autoimmune disease that destroys certain cells in the islets of Langerhans in the pancreas, where insulin is made. The lack of insulin leads to an excessive level of glucose in the blood (hyperglycemia), and to neurological, ocular, and kidney complications. Type 2 diabetes is provoked by a lack of response of the body to insulin, known as insulin resistance, due to both genetic and environmental factors (weight gain, sedentary lifestyle). It also leads to hyperglycemia and associated complications, and usually appears after the age of forty.

Notes :

1. Génomique et physiologie moléculaire des maladies métaboliques (CNRS / Université Lille-II / Institut Pasteur de Lille).
2. Thérapie cellulaire du diabète (CHRU de Lille / Université Lille-II/ Inserm).
3. Université Lille-II and Institut Pasteur de Lille.
4. Récepteurs nucléaires, maladies cardiovasculaires et diabète (Inserm / Institut Pasteur de Lille / Université Lille-II).

Contacts :

EGID, Lille.
Philippe Froguel,
François Pattou,
Bart Staels,
Jean-Benoist Duburcq,


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