Type 2 diabetes is characterized by insulin resistance of target organs, which is due to impaired insulin signal transduction. The skeleton of signaling mediators that provide for normal insulin action has been established. However, the detailed kinetics, and their mechanistic generation, remain incompletely understood. We measured time-courses in primary human adipocytes for the short-term phosphorylation dynamics of the insulin receptor (IR) and the IR substrate-1 in response to a step increase in insulin concentration. Both proteins exhibited a rapid transient overshoot in tyrosine phosphorylation, reaching maximum within 1 min, followed by an intermediate steady-state level after approximately 10 min. We used model-based hypothesis testing to evaluate three mechanistic explanations for this behavior: (A) phosphorylation and dephosphorylation of IR at the plasma membrane only; (B) the additional possibility for IR endocytosis; (C) the alternative additional possibility of feedback signals to IR from downstream intermediates. We concluded that (A) is not a satisfactory explanation; that (B) may serve as an explanation only if both internalization, dephosphorylation, and subsequent recycling are permitted; and that (C) is acceptable. These mechanistic insights cannot be obtained by mere inspection of the datasets, and they are rejections and thus stronger and more final conclusions than ordinary model predictions.

To be able to capture the dynamics of entire systems is one of the strengths of the Modelica language. This article will examine the possibility of modeling spur gears in the Modelica environment Wolfram System-Modeler, and integrating them with other rotating machinery elements, such as roller bearings and flexible shafts. The contact forces between spur gears are based on the Hertzian Theory of Contact 1

Robust state estimation for states evolving on compact manifolds is achieved by employing a point-mass filter. The proposed implementation emphasizes a sane treatment of the geometry of the problem, and advocates separation of the filtering algorithms from the implementation of particular manifolds.

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