Achieving Productive Beta-cell Proliferation

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Type 1 diabetes (T1D) mellitus is an autoimmune disease characterized by the destruction of beta-cells in the pancreatic islets, leading to insulin deficiency and hyperglycemia. Type 2 diabetes (T2D) commences with insulin resistance followed by beta-cell failure. Promoting the regeneration of functional beta-cells is recognized as a promising therapeutic avenue towards normalizing glycemic control in both type 1 and 2 diabetics. Regeneration is a process of controlled cell proliferation and differentiation that restores the entire tissue. While the role of differentiation in adult pancreas regeneration remains controversial, the role of beta-cell proliferation is well established. Thus, triggering beta-cell proliferation is considered a promising approach for regenerative therapy in diabetes. However, an important prerequisite for effective regeneration is that beta-cell proliferation is productive i.e. cell-cycle entry leads to a corresponding increase in beta-cell number. Notably, in the vast majority of cases, forcing cell-cycle entry in the beta-cells does not translate into increased beta-cell mass, indicating that cell-cycle entry might be unproductive. Thus, identifying the basic principles underlying the discrepancy between our ability to drive cell-cycle re-entry of beta-cells and the failure to achieve effective beta-cell mass expansion is an important and unexplored challenge for beta-cell regeneration. In our proposal, we will achieve the outstanding aim to be able to trigger productive beta-cell proliferation. To this, we will first identify the cellular and molecular players underlying unproductive proliferation using state-of-the art reporters in zebrafish and mouse beta-cells. Second, we will perform functional validation by overexpressing the genes or mutating them in zebrafish, mouse and human beta-cells. Finally, we will define pharmacological means and metabolic means for beta-cell protection from unproductive beta-cell proliferation. All in all, we will apply three different models, including zebrafish, mouse and human to address an outstanding question in the field.