A partial view of the mechanism of insulin action

Abstract

Insulin was discovered 60 years ago [1]; since then its structure has been determined by the pioneer work of Sanger [2] and by Hodgkin, Blundell and colleagues [3]. Moreover the principle effects of insulin on carbohydrate, fat and protein metabolism have been well recognised, at least ingeneral terms, for some 20 years [4][5][6][7], yet, we do not have a satisfactory description at the molecular level of how this hormone brings about its wide range of effects on target cells. This is certainly not due to any lack of attention to the problem by research workers. The literature on this subject is vast and, in the absence of any generally acceptable hypothesis, it also tends to be rather confused and certainly conflicting. Since it is quite unrealistic to survey the whole field, we make no apology for concentrating on certain aspects in this article.Insulin has both long and short term effects on the metabolism of its target cells. The long term effects involve changes in both general and specific protein synthesis and breakdown, while short term effects are those brought about solely through changes in the activity of pre-existing enzymes and membrane transporters. To a large extent, we will neglect all aspects of long term regulation including protein synthesis and amino acid metabolism. In fact, advances in these areas have been delayed by the lack of satisfactory preparations suitable for probing the mechanisms involved in the specific induction and repression of enzymes by insulin in vitro. This situation will probably change rapidly as a number of such preparations have been reported recently. Particularly promising are the 3T3-L1 preadipocyte cell line [8,9] and also the maintenance liver cell cultures from young rats in which glucokinase activity has been shown to be rapidly induced on exposure to insulin in the presence of glucose [10].In the rest of this review we will concentrate on those studies concerned with short term effects of insulin on carbohydrate and fat metabolism in the cells of liver, muscle and, particularly, adipose tissue. All these cells have specific insulin receptors on the outward face of the plasma membrane but we will not be considering the nature of these receptors nor their interaction with insulin nor the mechanisms which may govern the number of insulin receptors. These aspects have all been well covered in other recent reviews [11][12][13]. We shall address ourselves to the problem of the process or processes whereby alterations in the level of occupancy of the plasma membrane insulinreceptors lead to a wide range of intracellular changes. The assumption will be made that neither the whole insulin molecule nor part of it needsto enter the cells of its target tissue to bring about the effects of insulin. There seems little doubt that insulin bound to its receptor can be "internalized" into liver and probably other cells [14, 15], however, the process appears to be too slow to represent the means whereby insulin could bring about its short term effects. On the other hand, antibo...

The regulation of glucose transport in insulin-sensitive cells

“…These findings have supported the hypothesis that a phosphorylation cascade mediates and amplifies the intracellular action of insulin [56,57]. However, the mechanism of signal transduction from the receptor-mediated tyrosine phosphorylation to the rapid changes in glucose metabolism is still not completely understood.…”

Protein kinase activity of the insulin receptor

“…In contrast, the serine kinase would play a role in insulin's metabolic actions. All kinases involved in the control of intermediary metabolism are indeed serine-or threonine-specific (Denton et al, 1981;Cohen, 1982), and phosphoserine and phosphothreonine constitute about 99.97% of all phosphorylated amino acids, phosphotyrosine accounting for the remaining 0.03% (Hunter & Sefton, 1980). In the second model, the two kinases are activated sequentially.…”

“…The regulatory effects include activation of transport processes for glucose, amino acids and ions, regulation of enzyme activities involved in carbohydrate, lipid and protein metabolism and modulation of cell growth. These insulin actions show a variation in their time of onset and their dose-response relationship ranging from acute effects (seconds to minutes) on transport and enzyme systems at low insulin concentrations to slow promotion (hours) of cell proliferation at higher insulin levels Denton et al, 1981;Czech, 1984). The various effects of insulin on different cell types are mediated by membrane receptors which are homologous in their structural and functional characteristics.…”

“…This novel observation is of interest for our understanding of insulin-regulated processes, since it is now recognized that covalent phosphorylation-dephosphorylation of proteins is a mechanism whereby many cellular functions are regulated by hormones and neurotransmitters (Denton et al, 1981;Cohen, 1982;Houslay, 1981). Furthermore, protein kinases are also constituents of receptors for several polypeptide growth factors, including epidermal growth factor (EGF) (Cohen et al, 1980), platelet-derived growth factor (PDGF) (Ek et al, 1982), transforming growth factor (TGF-a) (Reynolds et al, 1981), and insulin-like growth factor I (IGF-I) (Jacobs et al, 1983, implying that receptor kinase activity may represent a general mechanism in transmembrane signalling of hormones and growth factors.…”

“…In spite ofthis progress the molecular mechanism of insulin action is still poorly comprehended regarding the events following the receptor binding and leading to the ultimate cellular responses. Possible mechanisms of intracellular signal transmission include changes in intracellular Ca2+ concentration, protein phosphorylation, release ofpeptide mediators, interaction with guanine nucleotide regulatory proteins and internalization of receptor-hormone complexes, but attempts to identify a second messenger in insulin action has so far been inconclusive (for reviews see Denton et al, 1981;Houslay, 1981;Houslay & Heyworth, 1983;Czech, 1984;Bergeron et al, 1985;Cheng & Lamer, 1985).…”