Key result
A multi-organ signalling network model of type 2 diabetes mellitus demonstrated robust bi-stability with distinct insulin-sensitive and insulin-resistant attractors, suggesting the disease's irreversibility is a network property.
A computational network model reveals that the irreversibility of T2DM is driven by the inter-organ signalling network structure rather than isolated insulin resistance, highlighting potential behavioral and neuro-endocrine targets for disease reversal.
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Suggests systemic network targeting may be required for T2DM reversal; leaves open whether these computational.
Type 2 diabetes mellitus (T2DM) is believed to be irreversible although no component of the pathophysiology is irreversible. We show here with a network model that the apparent irreversibility is contributed by the structure of the network of inter-organ signalling. A network model comprising all known inter-organ signals in T2DM showed bi-stability with one insulin sensitive and one insulin resistant attractor. The bi-stability was made robust by multiple positive feedback loops suggesting an evolved allostatic system rather than a homeostatic system. In the absence of the complete network, impaired insulin signalling alone failed to give a stable insulin resistant or hyperglycemic state. The model made a number of correlational predictions many of which were validated by empirical data. The current treatment practice targeting obesity, insulin resistance, beta cell function and normalization of plasma glucose failed to reverse T2DM in the model. However certain behavioural and neuro-endocrine interventions ensured a reversal. These results suggest novel prevention and treatment approaches which need to be tested empirically.
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Kulkarni et al. (2017) studied Type 2 diabetes mellitus. Network perturbation vs. Baseline state was evaluated on Network stability and attractor states. A multi-organ signalling network model of type 2 diabetes mellitus demonstrated robust bi-stability with distinct insulin-sensitive and insulin-resistant attractors, suggesting the disease's irreversibility is a network property.
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