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Molecular & Cellular Proteomics 4:441-457, 2005.
© 2005 by The American Society for Biochemistry and Molecular Biology, Inc.

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Review

Unraveling the Pathogenesis of Type 1 Diabetes with Proteomics: Present And Future Directions^*

Thomas Sparre^,, Martin R. Larsen^¶, Peter E. Heding, Allan E. Karlsen, Ole N. Jensen^¶ and Flemming Pociot

From the Steno Diabetes Center, DK-2820 Gentofte, Denmark; ^¶ Institute for Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense, Denmark

Type 1 diabetes (T1D) is the result of selective destruction of the insulin-producing ß-cells in the pancreatic islets of Langerhans. T1D is due to a complex interplay between the ß-cell, the immune system, and the environment in genetically susceptible individuals. The initiating mechanism(s) behind the development of T1D are largely unknown, and no genes or proteins are specific for most T1D cases. Different pro-apoptotic cytokines, IL-1 ß in particular, are present in the islets during ß-cell destruction and are able to modulate ß-cell function and induce ß-cell death. In ß-cells exposed to IL-1 ß, a race between destructive and protective events are initiated and in susceptible individuals the deleterious events prevail. Proteins are involved in most cellular processes, and it is thus expected that their cumulative expression profile reflects the specific activity of cells. Proteomics may be useful in describing the protein expression profile and thus the diabetic phenotype. Relatively few studies using proteomics technologies to investigate the T1D pathogenesis have been published to date despite the defined target organ, the ß-cell. Proteomics has been applied in studies of differentiating ß-cells, cytokine exposed islets, dietary manipulated islets, and in transplanted islets. Although that the studies have revealed a complex and detailed picture of the protein expression profiles many functional implications remain to be answered. In conclusion, a rather detailed picture of protein expression in ß-cell lines, islets, and transplanted islets both in vitro and in vivo have been described. The data indicate that the ß-cell is an active participant in its own destruction during diabetes development. No single protein alone seems to be responsible for the development of diabetes. Rather the cumulative pattern of changes seems to be what favors a transition from dynamic stability in the unperturbed ß-cell to dynamic instability and eventually to ß-cell destruction.

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