Summary and perspectives

Summary

Nearly two years ago, I wrote a short review article on the mechanism of action of insulin for the Nature (Espinal, 1987). Few things have changed since then, but what follows is an updated version of that article.

Insulin exerts a central physiological role in the regulation of numerous processes. The magnitude of its importance can be measured by the magnitude of the disease that its absence or inability to function causes. For anyone unsure of this, looking at the consequences of diabetes would assure them otherwise. The effects of insulin occur over a range of times and in many different tissues. At the molecular level, however, some common patterns emerge. Thus, most of the enzymes whose activity is modified by insulin are dephosphorylated in response to the hormone. A few exceptions exist, and indeed some proteins are phosphorylated, but the physiological relevance in these cases has not been demonstrated as yet.

In spite of the amount of knowledge we have about insulin, even now, more than sixty years after its discovery, the mechanism of action of this hormone continues to be a puzzle. Most hormones and other agonists need to bind to specific cell surface receptors in order to exert their cellular effects. This is the first required step in a long cascade of events. Indeed this is the case with insulin. The insulin receptor belongs to the tyrosine kinase family of cell surface receptors. The kinase is activated upon binding of insulin to its receptor and leads to the autophosphorylation of the receptor. The kinase uses the receptor itself as its main substrate, and there is some evidence that suggests that the receptor could be its only physiologically relevant substrate. Most evidence acquired to date suggests that the tyrosine kinase activity of the receptor is required for transmission of the signal. This has been confirmed by site-directed mutagensis and antibody studies. Some studies with monoclonal antibodies suggest the opposite, but the descriptions of defects in tyrosine kinase activity in patients with insulin resistance suggest a physiological and pathological relevance for the enzymatic activity.