Second messengers of insulin action.
Despite significant advances in past 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 the actions of insulin. 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 glycosylphosphatidylinositol 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-phosphatidylinositol 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 may be released from cells by a similar insulin-sensitive phospholipase-catalyzed reaction. Future efforts will focus on the precise role of the metabolism of glycosyl phosphatidylinositols in insulin action.
Saltiel
A R
AR
Rockefeller University, New York, NY 10021.
D000818:Animals; D004075:Diglycerides / Q000378:metabolism; D006017:Glycolipids / Q000378:metabolism; D017261:Glycosylphosphatidylinositols; D006801:Humans; D007328:Insulin / Q000502:physiology*; D008954:Models, Biological; D010716:Phosphatidylinositols / Q000378:metabolism; D011972:Receptor, Insulin / Q000502:physiology; D015290:Second Messenger Systems; D010738:Type C Phospholipases / Q000378:metabolism
D004075:Diglycerides; D006017:Glycolipids; D017261:Glycosylphosphatidylinositols; D007328:Insulin; D010716:Phosphatidylinositols; D011972:Receptor, Insulin; D010738:Type C Phospholipases