Towards a mechanistic explanation of insulin resistance, which incorporates mTOR, autophagy, and mitochondrial dysfunction

Sammanfattning: Type 2 diabetes is a global disease which affects an increasing number of peopleevery year. At the heart of the disease lies insulin resistance in the target tissues,primarily fat and muscle. The insulin resistance is caused by the failure of a complexsignalling network, and several mechanistic hypotheses for this failure havebeen proposed. Herein, we evaluate a hypothesis that revolves around the proteinmammalian target of rapamycin (mTOR) and its feedback signals to insulin receptorsubstrate-1 (IRS1). In particular, we have re-examined this hypothesis andrelevant biological data using a mathematical modelling approach. During the course of modelling we gained several important insights. For instance,the model was unable to reproduce the relation between the EC50-valuesin the dose-response curves for IRS1 and its serine residue 312 (Ser-312). Thisimplies that the presented hypothesis, where the phosphorylation of Ser-312 liesdownstream of the tyrosine phosphorylation of IRS1, is inconsistent with the provideddata, and that the hypothesis or the data might be incorrect. Similarly, wealso realized that in order to fully account for the information in the dose-responsedata, time curves needed to be incorporated into the model. A preliminary model is presented, which explains most of the data-sets, butstill is unable to describe all the details in the data. The originally proposed hypothesisas an explanation to the given data has been revised, and our analysisserves to exemplify that an evaluation of a mechanistic hypothesis by mere biochemicalreasoning often misses out on important details, and/or leads to incorrectconclusions. A model-based approach, on the other hand, can efficiently pin-pointsuch weaknesses, and if combined with a comprehensive understanding of biologicalvariation and generation of experimental data, mathematical modelling canprove to be a method of great potential in the search for mechanistic explanationsto the cause of insulin resistance in type 2 diabetics.