MANNOSE, GLUCOSAMINE AND INOSITOL MONOPHOSPHATE INHIBIT THE EFFECTS OF INSULIN ON LIPOGENESIS - FURTHER EVIDENCE FOR A ROLE FOR INOSITOL PHOSPHATE-OLIGOSACCHARIDES IN INSULIN ACTION

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  • 15 March 1990
    • journal article
    • research article
    • Vol. 266  (3) , 909-916
Abstract
The mechanism of insulin signalling is not yet understood in detail. Recently, a role for inositol phosphate (IP)-oligosaccharides as second messengers transmitting the insulin signal at the post-kinase level was proposed. To evaluate this hypothesis further, we studied whether IP-oligosaccharides isolated from ''haemodialysate'' have insulin-like activity. We found that these compounds mimic, in a dose-dependent fashion, the following effects of insulin in adipocytes. (1) Lipogenesis. Incorporation of [3H]glucose into lipids (expressed in nmol/min per 106 cells): basal, 0.74 .+-. 0.05; insulin (1 .mu.unit/ml), 4.43 .+-. 0.21; IP-oligosaccharide (2 .mu.g/ml), 4.07 .+-. 0.19. (2) Inhibition of isoprenaline (isoproterenol) (1 .mu.M)-stimulated cyclic AMP levels and lipolysis. Cyclic AMP (pmol/105 cells): basal 0.84 .+-. 0.05; isoprenaline, 4.03 .+-. 0.19; isoprenaline + insulin (200 .mu.units/ml), 2.06 .+-. 0.7; isoprenaline + IP-oligosaccharides (2 .mu.g/ml), 2.4 .+-. 0.29. Inhibition of lipolysis (.mu.mol of glycerol/mg of protein): isoprenaline (1 .mu.M), 166 .+-. 11; isoprenaline + insulin (150 .mu.units/ml), 53 .+-. 3.5; isoprenaline + IP-oligosaccharides (2 .mu.g/ml), 58 .+-. 5. (3) Stimulation of 3-O-methylglucose transport; basal, 9 .+-. 3%; insulin (1 .mu.unit/ml), 67 .+-. 4%, IP-oligosaccharides (2 .mu.g/ml), 54 .+-. 2%. To identify the active molecules of the IP-oligosaccharide fraction, competition experiments were performed. IP-oligosaccharide effects on lipogenesis were blocked by inositol monophosphate, glucosamine and mannose. In contrast, these compounds did not inhibit IP-oligosaccharide effects on membrane-mediated functions (3-O-methylglucose transport, cyclic AMP levels, lipolysis). We also found that the effect of insulin on lipogenesis was blocked by mannose, glucosamine and inositol monophosphate, whereas the insulin effects on 3-O-methylglucose, cyclic AMP and lipolysis were unaffected. The following conclusions were reached. (1) IP-oligosaccharides mimic the major metabolic effects of insulin in adipocytes. This is consistent with the proposed role of IP-oligosaccharides as second messengers of certain insulin effects. (2) Mannose and glucosamine are functionally important sugar residues for the effect of IP-oligosaccharide on lipogenesis. (3) The observation that mannose, inositol monophosphate and glucosamine block the action of insulin of on lipogenesis supports a role of mannose- and glucosamine-containing IP-oligosaccharides as second messengers for this insulin effect.