Abstract
Insulin rapidly stimulates GLUT4 translocation and glucose transport in fat and muscle cells. Signals from the occupied insulin receptor are translated into downstream signalling changes in serine/threonine kinases within timescales of seconds, and this is followed by delivery and accumulation of the glucose transporter GLUT4 at the plasma membrane. Kinetic studies have led to realisation that there are distinct phases of this stimulation by insulin. There is a rapid initial burst of GLUT4 delivered to the cell surface from a subcellular reservoir compartment and this is followed by a steady-state level of continuing stimulation in which GLUT4 recycles through a large itinerary of subcellular locations. Here, we provide an overview of the phases of insulin stimulation of GLUT4 translocation and the molecules that are currently considered to activate these trafficking steps. Furthermore, we suggest how use of new experimental approaches together with phospho-proteomic data may help to further identify mechanisms for activation of these trafficking processes.
Highlights
In the 100th year of the discovery of insulin we reflect on a famous cartoon of the 1970s in which ‘Chuck’ describes the black box theory of insulin action and the following sequence: insulin binds to its receptor; something happens; cellular effects [1]
Very early in these studies it became evident that insulin stimulation of glucose uptake and GLUT4 translocation is a very fast process, and that maximum glucose uptake is achieved within 10 min of insulin binding to its receptor (Table 1)
In section ‘Considering kinetics of insulin-stimulated GLUT4 translocation’, we have proposed an updated model of GLUT4 traffic that includes a ‘retention-catalyst’ that is required for GLUT4 storage vesicles (GSVs) formation and sequestration
Summary
In the 100th year of the discovery of insulin we reflect on a famous cartoon of the 1970s in which ‘Chuck’ describes the black box theory of insulin action and the following sequence: insulin binds to its receptor; something happens; cellular effects [1]. Since the discovery of GLUT4 in the late 1980s [4,5,6], studies have shed light on the GLUT4 complex intracellular trafficking itinerary that effectively excludes GLUT4 from the PM in the absence of insulin and provides a large reservoir of GLUT4 that can be readily mobilised in response to insulin Very early in these studies it became evident that insulin stimulation of glucose uptake and GLUT4 translocation is a very fast process, and that maximum glucose uptake is achieved within 10 min of insulin binding to its receptor (Table 1). Studies using the PI3K inhibitors wortmannin [8] and LY294002 [9] and an
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