Proposal for a pathway to mediate the metabolic effects of insulin.
This review seeks to assemble recent discoveries about insulin receptor/kinase, guanine nucleotide-binding proteins, phosphatidyl inositol metabolism, and protein phosphatases to provide a mechanistic pathway by which insulin would alter carbohydrate and fat metabolism. It proposes a hypothetical chain of events that leads from the insulin receptor to protein phosphatase-1. The sequence starts with insulin binding to its receptor, activating the intrinsic receptor/kinase activity. The insulin receptor phosphorylates a guanine nucleotide-binding protein, which activates a particular phospholipase C. This in turn stimulates the production of two lipid-derived messengers: inositol-phospho-glucosamine and diacylglycerol. These messengers trigger the effects of insulin. The diacylglycerol produced by insulin is thought to be analogous to the diacylglycerol produced by alpha-adrenergic stimulation, which activates protein kinase C. Activation of this kinase could account for increases in phosphorylation of certain proteins. The inositol-phospho-glucosamine is the cytosolic messenger for insulin. One of the enzymes activated by insulin is protein phosphatase type-1. It is known that the phosphatase decreases phosphorylation of certain target enzymes. In response to insulin, activation of protein phosphatase type-1 occurs with a stable conformational change that may involve rearrangement of disulfide bonds. Rearrangement is either directly in response to the cytosolic messenger or is catalyzed by an isomerase activated by the insulin messenger. Ultimately, protein phosphatase type-1 and/or the disulfide isomerase may together mediate the pleiotropic effects of insulin on carbohydrate and fat metabolism.
Brautigan
D L
DL
Section of Biochemistry, Brown University, Providence, RI 02912.
Kuplic
J D
JD
D000818:Animals; D004220:Disulfides / Q000378:metabolism; D004734:Energy Metabolism; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007536:Isomerism; D008954:Models, Biological; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054645:Protein Phosphatase 1; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000032:analysis / Q000378:metabolism
D004220:Disulfides; D007328:Insulin; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1