Further evidence for a two-step model of glucose-transport regulation. Inositol phosphate-oligosaccharides regulate glucose-carrier activity.
The insulin effect on glucose uptake is not sufficiently explained by a simple glucose-carrier translocation model. Recent studies rather suggest a two-step model of carrier translocation and carrier activation. We used several pharmacological tools to characterize the proposed model further. We found that inositol phosphate (IP)-oligosaccharides isolated from the drug Actovegin, as well as the alkaloid vinblastine, show a partial insulin-like effect on glucose-transport activity of fat-cells (3-O-methylglucose uptake, expressed as % of equilibrium value per 4 s: basal 5.8%, insulin 59%, IP-oligosaccharides 30%, vinblastine 29%) without inducing carrier translocation. On the other hand, two newly developed anti-diabetic compounds (alpha-activated carbonic acids, BM 130795 and BM 13907) induced carrier translocation to the same extent as insulin and phorbol esters [cytochalasin-B-binding sites in plasma membranes: basal 5 pmol/mg of protein, insulin 13 pmol/mg of protein, TPA (12-O-tetradecanoylphorbol 13-acetate) 11.8 pmol/mg of protein, BM 130795 10.8 pmol/mg of protein], but produce also only 40-50% of the insulin effect on glucose-transport activity (basal 5.8%, insulin 59%, TPA 23%, BM 130795 35%). Almost the full insulin effect was mimicked by a combination of phorbol esters and IP-oligosaccharides (basal 7%, insulin 50%, IP-oligosaccharides 30%, TPA 23%, IP-oligosaccharides + TPA 45%). None of these substances stimulated insulin-receptor kinase in vitro or in vivo, suggesting a post-kinase site of action. The data confirm the following aspects of the proposed model: (1) carrier translocation and carrier activation are two independently regulated processes; (2) the full insulin effect is mimicked only by a simultaneous stimulation of carrier translocation and intrinsic carrier activity, suggesting that insulin acts through a synergism of both mechanisms; (3) IP-oligosaccharides might be involved in the transmission of a stimulatory signal on carrier activity.
Obermaier-Kusser
B
B
Institut für Diabetesforschung, München, Federal Republic of Germany.
Mühlbacher
C
C
Mushack
J
J
Seffer
E
E
Ermel
B
B
Machicao
F
F
Schmidt
F
F
Häring
H U
HU
D019325:3-O-Methylglucose; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003571:Cytochalasin B / Q000378:metabolism; D007295:Inositol Phosphates / Q000494:pharmacology*; D008757:Methylglucosides / Q000493:pharmacokinetics; D008956:Models, Chemical; D009004:Monosaccharide Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D009844:Oligosaccharides / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011972:Receptor, Insulin / Q000378:metabolism
D007295:Inositol Phosphates; D008757:Methylglucosides; D009004:Monosaccharide Transport Proteins; D009844:Oligosaccharides; D019325:3-O-Methylglucose; D003571:Cytochalasin B; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin