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Development of novel treatment strategies based on knowledge of cellular dysfunction in diabetes
figure: proposed
model for crosstalk between beta cells, BAT and WAT leading to cellular dysfunction in diabetes

The European project BetaBat (topic HEALTH.2011.2.4.3-2) aims to develop new treatment strategies based on knowledge of cellular dysfunction in diabetes. It is a collaborative projects with a duration of 4 years (start October 2011) and a budget of 6 million euro. It is coordinated by Prof. Décio L. Eizirik (U.L.B.) and includes partners from Belgium (3), Germany (2), U.K. (2), Finland (1), Spain (1), Sweden (1), Switzerland (1) and U.S.A. (1).

Concept : The global prevalence of diabetes has reached 285 million and is projected to rise to 435 million by 2030. Around 85% of patients have type 2 diabetes (T2D) and 10-15% type 1 diabetes (T1D). A reduction in functional pancreatic beta cell mass, caused by progressive loss of beta cell function and apoptosis, is the key feature of both T1D and T2D. Beta cell failure is exacerbated in the context of obesity and insulin resistance, and strategies promoting weight loss and energy dissipation have beneficial effects on beta cell function. Brown adipose tissue (BAT) is a highly metabolic organ that mediates energy dissipation and glucose disposal, and thus contributes to maintain an adequate energy balance and carbohydrate homeostasis. Conversely, there is evidence that BAT dysfunction promotes obesity and impairs carbohydrate metabolism, ultimately resulting in increased functional demand on the beta cells. Hence, we hypothesise that a deleterious metabolic "crosstalk" between beta cells and BAT will perpetuate/aggravate cellular dysfunction in diabetes. We propose the integrative concept that crosstalk between defective key gene and metabolic networks and/or insufficient protective responses (e.g. particular susceptibility to organelle dysfunction, low antioxidant defences) will increase the functional vulnerability of the beta cell and in severe cases lead to apoptosis. This crosstalk is modulated by the genetic background of the individuals at risk.

Objectives : We will perform a detailed "organelle diagnosis" based on both focused and systems biology approaches, which will provide the scientific rationale for the design of specific interventions to boost the capacity of beta cells and brown adipocytes to regain homeostatic control. We propose that only by understanding the complex molecular mechanisms triggering cellular dysfunction in diabetes, and by integrating this knowledge at the systems level, will it be possible to develop interventional therapies that protect and restore beta cell and BAT function. The ultimate goal is to offer individual therapeutic choices based on both genetic information and organelle diagnosis.