In search of a second messenger for insulin.
Despite significant advances in the past few years on the chemistry and biology of insulin and its receptor, the molecular events that couple the insulin-receptor interaction to the regulation of cellular metabolism remain uncertain. Progress in this area has been complicated by the pleiotropic nature of insulin's actions. These most likely involve a complex network of pathways resulting in the coordination of mechanistically distinct cellular effects. Because the well-recognized mechanisms of signal transduction (i.e., cyclic nucleotides, ion channels) appear not to be central to insulin action, investigators have searched for a novel second messenger system. A low-molecular-weight substance has been identified that mimics certain actions of insulin on metabolic enzymes. This substance has an inositol glycan structure and is produced by the insulin-sensitive hydrolysis of a glycosyl-phosphatidylinositol in the plasma membrane. This hydrolysis reaction, which is catalyzed by a specific phospholipase C, also results in the production of a structurally distinct diacylglycerol that may selectively regulate one or more of the protein kinases C. The glycosyl-phosphatidyl-inositol precursor for the inositol glycan enzyme modulator is structurally analogous to the recently described glycosyl-phosphatidylinositol membrane protein anchor. Preliminary studies suggest that a subset of proteins anchored in this fashion might be released from cells by a similar insulin-sensitive, phospholipase-catalyzed reaction. Efforts are underway to determine the precise role of the metabolism of glycosyl-phosphatidylinositols in insulin action.
Saltiel
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AR
Rockefeller University, New York, New York 10021.
Cuatrecasas
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D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D007295:Inositol Phosphates / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D008954:Models, Biological; D010716:Phosphatidylinositols / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
D007295:Inositol Phosphates; D007328:Insulin; D010716:Phosphatidylinositols; D011134:Polysaccharides; D011493:Protein Kinase C; D010738:Type C Phospholipases; D015105:3',5'-Cyclic-AMP Phosphodiesterases