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INTEGRATION OF THE SYSTEM MODELS OF INSULIN SIGNALLING AND OF MITOCHONDRIAL FUNCTION AND ITS APPLICATION IN THE STUDY OF COMPLEX DISEASES

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Insulin signalling and mitochondrial function interplay

A common phenomenon in disorders such as type 2 diabetes or obesity is the development of insulin resistance. European scientists investigated the cross-talk between insulin signalling and mitochondria function.

Fundamental Research
Health

New profiling technologies have entered the biomedical field, generating an unprecedented plethora of data. Computational tools capable of data mining are needed to integrate network information into meaningful models. Type 2 diabetes has reached epidemic proportions. Emerging evidence suggests that alterations in mitochondrial function may trigger the development of insulin resistance and conversely, insulin signalling has a direct impact on mitochondrial function. To clarify this interplay, the EU-funded MITIN (Integration of the system models of insulin signalling and of mitochondrial function and its application in the study of complex diseases) project investigated mitochondrial-dependent mechanisms responsible for the development of insulin resistance. The consortium followed a systems biology approach and generated computer-based tools to study complex biological systems and regulatory networks. Researchers developed a computational framework that integrated existing knowledge on gene expression, proteins or metabolites of insulin signalling and mitochondrial processes. Data generated during the MITIN project by transcriptomics and lipidomics analysis was also incorporated in the framework. The focus on lipid profiling was based on the capacity of insulin and mitochondria to modify lipid metabolism as well as determine the role of lipids in insulin sensitivity. The generated computer tool allowed the functional association between the two processes, which were tested under specific hypothesis-driven studies in mammalian cells, mice and Drosophila. Scientists examined the effect of specific perturbations in the insulin signalling pathway on mitochondrial function as well as how primary defects in mitochondria function affect insulin signalling. This tool further allowed scientists to simulate different complex metabolic and regulatory scenarios under disease conditions and identify the molecular perturbations. Overall, the computer-based MITIN tool demonstrated that it can be translated to human diabetes or related diseases. The associations detected during the MITIN project will generate high value targets for treating complex diseases such as diabetes, obesity, and the metabolic syndrome.

Keywords

Insulin signalling, mitochondria, type 2 diabetes, MITIN, computational framework

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