Insulin Model.

The top left plots show two datasets for evaluating the amount of insulin binding to individual cells by flow cytometry (FACS). The upper panel exemplarily shows the raw measurements five minutes after stimulation with 100 nM, the lower panel for 1000 nM. Independent of time and insulin dose, a bimodal distribution was observed indicating two entities of hepatocytes. Two Gaussian distributions were fitted to the logarithmic intensity histograms to analyze the time and dose dependency of the average insulin binding within both entities. The top right sketch shows the structure of the model for cellular insulin binding, internalization and extraction processes described by Eq 21 including the parameters given in Eq 22. This model could explain the dynamics for both entities of hepatocytes as seen in the bottom plot showing the model fit of time-dependent average insulin binding of both entities for three different doses. The experimentally observed data for low-binding and high-binding hepatocytes is shown as ‘+’ and ‘×’, respectively. Model predictions for these cases are solid and dashed lines, respectively. The shaded error bands correspond to the estimated error in the data points.