Direct comparison of inositol phosphoglycan with prostaglandylinositol cyclic phosphate, two potential mediators of insulin action.
Though insulin signalling is thought by many groups to function without second messenger action, others have provided evidence for the existence and action of such regulators. Chemically quite different compounds, however, have been proposed as mediators, such as various inositol phosphoglycans and prostaglandylinositol cyclic phosphate (cyclic PIP). In spite of marked structural differences, these compounds are reported to have the same regulatory properties, i.e. to activate protein ser/thr phosphatases and to inhibit protein kinase A. In order to clarify this discrepancy, the regulatory potency of these different compounds was assayed under identical conditions. It was found that in contrast to cyclic PIP, the synthetic inositol phosphoglycan PIG41 neither directly inhibited protein kinase A nor activated protein ser/thr phosphatases. However, when added to intact cells, such as primary adipocytes, PIG41 inhibited isoproterenol-stimulated lipolysis. This effect most likely results from tyrosine phosphorylation of insulin receptor substrates (IRSs) by PIG41. This tyrosine phosphorylation is not carried out by the insulin receptor tyrosine kinase but by cytosolic tyrosine kinases. This indicates that cyclic PIP, an intracellular regulator, which primarily acts on protein kinase A and on protein ser/thr phosphatases, operates more downstream in the signal transduction cascade as compared to the inositol phosphoglycan PIG41. Thus, cyclic PIP appears to be a suitable candidate to close the gap between IRSs and the protein kinases/phosphatases involved in the signal transduction of insulin.
Wasner
H K
HK
Deutsches Diabetes-Forschungsinstitut, Abteilung für klinische Biochemie und Pathobiochemie, Düsseldorf, Germany. heinrich.wasner@ddfi.uni-duesseldorf.de
Müller
G
G
Eckel
J
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002417:Cattle; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007295:Inositol Phosphates / Q000494:pharmacology*; D007700:Kinetics; D018482:Muscle, Skeletal / Q000201:enzymology; D011134:Polysaccharides / Q000494:pharmacology*; D011458:Prostaglandins E / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism
D007004:Hypoglycemic Agents; D007295:Inositol Phosphates; D011134:Polysaccharides; D011458:Prostaglandins E; C028039:inositol phosphate glycan; C052775:prostaglandin-inositol cyclic phosphate; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases