Strategies to modulate the pancreatic beta-cell mass to prevent type 1 diabetes

Type 1 diabetes (T1DM) results from the autoimmune destruction of most insulin-producing pancreatic beta-cells. For affected patients, diagnosis of T1DM represents the beginning of a life-long treatment with insulin. Insulin permits survival but mean life expectancy of diabetic patients remains shorter than in controls and the treatment has a significant impact on the patients' quality of life. There is urgent need for strategies aiming at preventing the destruction of the pancreatic beta-cells or even at restoring a functional beta-cell mass after diagnosis of the disease. The aim of this thesis is to review the current knowledge about the risk factors for T1DM, as well as about the molecular pathways leading to the destruction of the insulin-producing beta-cells. Four articles are presented. They focus on the identification of mechanisms permitting either the modulation of the beta-cell mass or the modulation of the beta-cell sensitivity to cytokines such as interleukin 1β (IL-1β), tumor necrosis factor α (TNFα) and interferon γ (IFNγ), all of which being implicated in the beta-cell destruction in a context of T1DM. The work underlying this thesis opens the basis for further studies aiming at dissecting the mechanisms by which pharmacological agonists may modulate the resistance of pancreatic beta-cells against auto-immune attacks. Moreover, since beta-cell apoptosis in a context of type 2 diabetes (T2DM) shares common pathways with cell death observed in T1DM, it would be important to determine whether the protective mechanisms identified in this thesis may also apply to glucotoxicity, lipotoxicity and low grade inflammation, as seen in T2DM