Public Release: 

Diabetes: Cholera Toxin Lends A Hand

French National Institute for Health and Medical Research (INSERM)

Charles Thivolet (INSERM Unit 449, Molecular Mechanisms of Diabetes, directed by Jean-Paul Riou in Lyon) is developing a new way to prevent diabetes by protecting insulin-producing pancreatic cells through oral insulin administration. In an article published in PNAS, he reports that the action of insulin can be amplified by concomitantly stimulating the immune system with cholera toxin.

Type I diabetes, an autoimmune disease that affects approximately 200 000 people in France, is due to the destruction of insulin-producing B cells in the pancreas by the immune system (cytotoxic lymphocytes). The only treatment is regular insulin injections.

Strategies being developed to fight this disease include B cell protection by a sort of "immune counterattack". Oral insulin administration has a "vaccinal" effect, provoking an immune reaction when it comes into contact with cells of the intestinal mucosa. Activated lymphocytes trigger the production of antiinflammatory cytokines that protect pancreatic B cells. The underlying mechanisms are unclear, but clinical trials of this approach, first tested in mice, are currently underway in the United States and France. One of the main problems is that large quantities of insulin have to be administered by mouth for several years.

Charles Thivolet (INSERM 449, Lyon), in collaboration with Cecil Czerkinsky (Göteborg University, Sweden), has found an original solution to this obstacle by combining insulin with CTB, the non toxic B subunit of cholera toxin. The aim is to amplify the immune reaction and thereby to obtain similar efficacy with a far lower dose of insulin. The work published in PNAS was based on the NOD diabetic mouse model, treated before the onset of diabetes. After fifteen weeks of treatment, only 2 of the 17 animals in the group treated with insulin and CTB had developed diabetes, compared to 7 of the 16 control animals treated with CTB alone. According to Charles Thivolet, these results are similar to those obtained in other studies in which milligram doses of insulin alone were given for several weeks, whereas he administered only micrograms of insulin in a single intake.

Studies will now focus on the mechanisms underlying the action of this insulin-CTB combination before clinical trials are envisaged.

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References
A Cholera toxoid-insulin conjugate as an oral vaccine against spontaneous autoimmune diabetes
Proc. Natl. Acad. Sci (PNAS) USA, Vol. 94, pp. 4610-46114, April 28 1997
Isabelle Bergerot*, Corinne Ploix*, Jacob Peterseny, Valérie Moulin*, Carola Rask, Nicole Fabien*, Marianne Lindblad, Anne Mayer*, Cecil Czerkinsky#**, Jan Bolmgren and Charles Thivolet*

* INSERM Unit 499, Faculté Alexis Carrel, Lyon, France y Zymogenetics, Seattle, WA 98102, USA
# INSERM, Edouard Herriot Hospital, Lyon, France
** Department of Medical Microbiology and Immunology, Guldhedsgatan, University of Göteborg, Sweden


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