In the early 1980s two important discoveries revealed the beginning and end of a cascade of reactions that link the interaction of insulin with its receptor and the stimulation of the uptake of glucose into mammalian cells. First, Kasuga et al.[1, 2] discovered that the occupied insulin receptor is a tyrosine kinase leading to both tyrosine autophosphorylation of the receptor b-subunit and of cellular substrates. Second, Cushman and Wardzala [3] and Suzuki and Kono [4] discovered that glucose transporters are mainly resident in intracellular membrane vesicles in the absence of insulin and that insulin stimulation leads to an increase in the recruitment of these transporters to the plasma membrane. This translocation accounts for the increased rates of glucose transport into the stimulated cells. Details have emerged concerning both the beginning and end of the cascade and gradually the intermediate events in signalling and glucose transporter recruitment are being elucidated. The success in identifying these intermediate steps has not been as rapid as that which has led to the elucidation of the intermediate signalling events involved in stimulation of cell growth and mitosis. In this cascade, a key switch in signalling occurs between tyrosine kinase activation and serine/threonine kinase activation. The switch occurs through the G-protein

Ras which activates downstream Raf and mitogen activated protein (Map) kinases [5–8]. Such a switch has not been demonstrated for the reactions leading to stimulation of glucose transport and, as we describe below, there is evidence that the Map kinase pathway is not involved in the activation process. The divergence of mitotic stimulation and metabolic stimulation (via increased glucose transport) is clearly necessary in the insulin-target tissues of muscle and fat where there is a requirement that increased metabolic flux is acutely regulated over short timescales without a concomitant stimulation of cell growth and division. The extent to which these two signalling pathways diverge has also been difficult to dissect as studies of cell culture models and cell free systems have suggested that there is the potential for cross-talk between these two pathways. Such crosstalk may be less significant in cells that are specialised to perform discrete functions. Given the complexity of the possible interactions between signalling intermediates, the mapping of a direct cascade leading to increased glucose transport is at present incomplete. Therefore, this review describes some of the advances that have been made in the search for intermediates which lead to glucose transporter translocation and speculates on possible mechanisms and missing links that may be involved in the complete signalling pathway.