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AstraZeneca postdoc grant

This project is a collaboration between AstraZeneca and Gunnar Cedersund, funed by AstraZeneca, to use quntitative mechanistic modeling of glucose and lipid metabolism to identify and evaluate novel diabetes targets.

Type 2 diabetes mellitus (T2DM) is a systems disease affecting multiple cell types and organs, and characterized by insulin resistance in peripheral tissues. Intracellular mechanisms involved in insulin signaling are complex and investigation of mechanistic hypotheses can be significantly facilitated by mathematical modeling. A quantitative model of the intracellular mechanisms involved in glucose uptake and insulin resistance, was recently reported based on in vitro and in vivo data from T2DM and non-diabetic individuals [1]. The authors also propose unexplored drug targets for insulin-sensitization. However, this model does not describe the important anti-lipolytic effect of insulin signaling in adipocytes. The crosstalk between the insulin signaling pathways and lipid metabolism may include potential insulin resistance mechanisms, as well as anti-lipolytic targets. Also, the quantitative model [1] lacks the systemic whole-body regulation of fatty acid (FA) metabolism. In the postprandial state, fatty acid dynamics are interconnected with the plasma glucose response due to the reciprocal regulation between glucose and FA concentrations and the central role of insulin in the homeostasis of both metabolites. A development of the model in [1], including intracellular lipid metabolism as well as systemic FA regulation, would provide a novel possibility for drug target evaluation in metabolic diseases, as well as provide a novel tool for translating preclinical findings prior to evaluation in vivo in humans.

This project will extend the state-of–the-art insulin signaling/T2DM model [1] to include intracellular mechanisms of lipid metabolism, and link these results to the systemic fatty acid metabolism, using the approach in [6]. Using data for cAMP levels, glycerol release, and fatty acid release, collected at Linköping University and AstraZeneca, the mechanistic insulin signaling model [1] will be extended to also include stimulation of lipolysis via isoproterenol and the antilipolytic actions of insulin via PKB/PDE3B. The project will include the techniques of the ISB group and different mechanisitc hypothesises will be tested against the collected knowledge at Linköping's University and AstraZenca, and the experimental data. The hypothesis testing approach will be used to evaluate the importance of different mechanisms and crosstalk in the intracellular insulin signaling/lipolysis pathways.

A dynamic whole-body model that incorporates glucose, insulin and fatty acid metabolism in the postprandial state, normally and in T2DM, will also be developed. The whole-body model will be based on a state-of-the-art meal response insulin/glucose model [2], a phenomenological model of glucose and FA dynamics [4], and a model of insulin-regulated postprandial FA dynamics [5]. The combination of these models will provide a first FA/insulin/glucose model for the postprandial state. The FA/insulin/glucose model can also be extended to describe other interesting states such as fasting, exercise, and multiple meals. The next step in the modeling process is to integrate the developed mechanistic intracellular lipolysis model with the developed FA/insulin/glucose model. This integration will be based the approach in [6], where data/model simulations from the whole-body level are used as constraints for the intracellular model. The integration of models will be facilitated by the use of both intracellular data and clinical data for FA, insulin, and glucose. The multilevel modeling software Wolfram SystemModeler will be used for the integration. With the combined insulin signaling/lipolysis and FA/insulin/glucose model the effect of changes at the intracellular level will be simulated, and the effect on the systemic levels and regulations will be observed. Different mechanisms of restoring the insulin sensitive state at the intracellular level will be explored, and the whole-body effects of such restoration.

References

1. Brännmark, C., Nyman, E., Fagerholm, S., Bergenholm, L., Ekstrand, E. M., Cedersund, G. & Strålfors, P. (2013) Insulin signaling in type 2 diabetes: experimental and modeling analyses reveal mechanisms of insulin resistance in human adipocytes, J Biol Chem. 288, 9867-80.
2. Dalla Man, C., Rizza, R. A. & Cobelli, C. (2007) Meal simulation model of the glucose-insulin system, IEEE Trans Biomed Eng. 54, 1740-9.
3. Kovatchev, B. P., Breton, M. D., Dalla Man, C. & Cobelli, C. (2008) In silico model and computer simulation environment approximating the human glucose/insulin utilization, Food and Drug Administration Master File MAF 1521.
4. Roy, A. & Parker, R. S. (2006) Dynamic modeling of free fatty acid, glucose, and insulin: an extended "minimal model", Diabetes technology & therapeutics. 8, 617-26.
5. Jelic, K., Hallgreen, C. E. & Colding-Jorgensen, M. (2009) A model of NEFA dynamics with focus on the postprandial state, Ann Biomed Eng. 37, 1897-909.
6. Nyman, E., Brännmark, C., Palmér, R., Brugård, J., Nyström, F. H., Strålfors, P. & Cedersund, G. (2011) A hierarchical whole-body modeling approach elucidates the link between in Vitro insulin signaling and in Vivo glucose homeostasis, J Biol Chem. 286, 26028-41.