Comme nous avons pu le voire lors des paragraphes précédents, une hyperglycémie chronique est capable d’induire d’importantes perturbations de la sécrétion d’insuline. La modulation de l’expression de plusieurs protéines des cellules ȕ, lors d’une hyperglycémie chronique, pourrait expliquer cette toxicité du glucose [44].
Au niveau des granules de sécrétion à insuline, il est connu que certaines protéines de cette organelle jouent un rôle essentiel dans le bon fonctionnement de la libération de l’insuline [71, 75]. De plus, il a été montré que le glucose est capable de moduler l’expression de certaines protéines des granules à insuline [79]. Cependant, au début de ce travail de thèse, les identités et les fonctions de nombreuses protéines des granules à insuline restaient inconnues, puisque seule une petite partie du protéome de cette organelle était connue.
Nous avons ainsi émis l’hypothèse que la modulation de l’expression de certaines protéines encore inconnues des granules à insuline, pourrait être en partie responsables des perturbations de la sécrétion d’insuline observées lors d’une hyperglycémie chronique.
Le but de ce travail de thèse a consisté à établir à partir de la lignée cellulaire ȕ INS-1E, l’identité des ces protéines, grâce à des techniques de spectrométries de masse et de biologie cellulaires et moléculaires.
Ce manuscrit de thèse se divise ainsi en 5 grandes parties:
1) Trois études bibliographiques correspondants à:
i) Chapitre II: Un chapitre de livre publié portant sur les différentes méthodes pouvant être employées lors d’analyses protéomiques.
ii) Chapitre III: Un manuscrit soumis pour publication portant sur les différents mécanismes impliqués dans le contrôle de la glycémie ainsi que dans le développement de la glucotoxicité.
Différents travaux publiées portant sur l’étude de la glucotoxicité envers les cellules pancréatiques, grâce à des méthodes protéomiques, sont également présentés dans ce manuscrit.
iii) Chapitre IV: Un manuscrit soumis pour publication présentant les principaux mécanismes régulant la sécrétion cellulaire. Différentes analyses protéomiques de vésicules sécrétoires sont également présentées dans ce manuscrit (chapitre IV).
Ces trois chapitres permettent de compléter le chapitre d’introduction de ce manuscrit de thèse.
2) La caractérisation du protéome des granules à insuline qui a permis de mettre en évidence la colocalisation avec les granules à insuline de nouvelles protéines. Ce travail a été publié en 2007 dans Molecular and Cellular Proteomics et correspond au chapitre V de ce manuscrit de thèse.
3) L’étude des modifications quantitatives du protéome des granules à insuline en réponse à une hyperglycémie chronique. Dans un premier temps, l’effet de la présence d’acides aminés isotopiques sur l’expression des gènes et des protéines des cellules INS-1E a été étudié. Un manuscrit présentant ces résultats a été soumis au journal «Nature Methods» et correspond au chapitre VI de ce manuscrit de thèse. Dans un deuxième temps, les conditions d’hyperglycémie cellulaire ont été déterminées et les protéines dont l’expression est modulée par cette hyperglycémie chronique ont été identifiées par spectrométries de masse. Ces résultats sont présentés dans le chapitre VII de ce manuscrit de thèse.
4) L’étude de l’une des protéines, nommée ProSAAS, trouvée sous-exprimée en réponse à une hyperglycémie chronique des cellules ȕ. Cette étude a consisté à déterminer la localisation de la protéine, ainsi que son expression en fonction de la concentration de glucose. Enfin, une étude a été débutée afin d’étudier le rôle de la ProSAAS dans la sécrétion d’insuline des cellules INS-1E.
L’ensemble de ces résultats se retrouvent dans le chapitre VII de manuscrit de thèse.
5) Une discussion générale sur l’ensemble des résultats obtenus lors de ce travail de thèse est présentée dans le chapitre VIII de ce manuscrit.
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