A reduction in functional pancreatic beta cell mass is the key feature of type 1 and type 2 diabetes. Beta cell failure is exacerbated in the context of obesity and insulin resistance. Brown adipose tissue (BAT) is a highly metabolic organ, mediating energy dissipation and glucose disposal, thus contributing to maintain energy balance. BAT dysfunction contributes to obesity and impaired glucose metabolism, increasing functional demand on the beta cells. The cellular dysfunction of beta cells and BAT in diabetes is the fruit of defective signal transduction and organelle function, and the vulnerability to these molecular defects may be modulated by diabetes genes. To identify the crosstalk and pathways responsible for beta cell and BAT dysfunction and beta cell apoptosis in diabetes at its real level of complexity, this consortium will use cutting edge genetics, functional (epi)genomics, molecular biology and computational tools to reach an accurate organelle and cell diagnosis. This diagnosis will be used to define novel targets for intervention to prevent dysfunction and facilitate recovery of functionally impaired metabolic tissues. Some of these targets have already been identified by consortium members, including endoplasmic reticulum (ER) stress and mitochondrial dysfunction and apoptosis. Since many of these targets are related to dysfunction of specific organelles, we will focus on the novel concept of organelle therapy, aiming to preserve mitochondrial and ER function by the use of viral vectors and small molecule chemical probes. We will thus follow a two-pronged approach, namely a focused approach to restore known and specific cellular/organelle dysfunctions and a systems biology approach to identify novel targets for intervention. This, in combination with high throughput screening of large compound libraries, will translate discoveries into innovative therapeutic strategies that halt destruction and facilitate recovery of cell dysfunction in diabetes.
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