Speaker
Description
In mammalian fat cells, insulin regulates glucose uptake by controlling the trafficking of the glucose transporter GLUT4 between intracellular compartments and the plasma membrane. Under basal conditions, GLUT4 is largely sequestered in slowly cycling pools, but insulin stimulates its mobilisation, exocytosis, and cycling, with rapid re-sequestration following insulin withdrawal.
Structural motifs of GLUT4, including the LL and FQQI sequences, govern GLUT4 targeting to insulin responsive compartments; mutations such as LLAA or AQQI are thought to disrupt sorting and produce impaired insulin responsiveness.
To quantify these dynamics, we model GLUT4 trafficking in 3T3-L1 adipocytes using parsimonious compartmental models in which insulin modulates the exocytosis rate constant and the distribution of GLUT4 between cycling and non-cycling pools. Model optimisation of steady state and transition data supports a dose dependent expansion of the cycling pool at submaximal insulin levels and indicates that insulin also regulates a second kinetic rate constant. The model is then extended to include perturbations to the trafficking kinetics due to mutations of GLUT4 motifs.
Different approaches to parameter inference simultaneously constrained by multiple experimental data sets are discussed and the effects of structural motifs and dynamic regulation of GLUT4 trafficking under varying insulin concentrations and mutations is explored.
