Abstract
We have used SV40-transformed hepatocytes from insulin receptor-deficient mice (-/-) and normal mice (WT) to investigate the different abilities of insulin and IGF-1 receptors to stimulate glycogen synthesis. We report that insulin receptors are more potent than IGF-1 receptors in stimulating glycogen synthesis. Both receptors stimulate glycogen synthesis in a PI 3-kinase-dependent manner, but only the effect of insulin receptors is partially rapamycin-dependent. Insulin and IGF-1 receptors activate Akt to a similar extent, whereas GSK-3 inactivation in response to IGF-1 is considerably lower in both -/- and WT cells, compared to the effect of insulin in WT cells. The findings indicate that (i) the potency of insulin and IGF-1 receptors in stimulating glycogen synthesis correlates with their ability to inactivate GSK-3, (ii) the extent of GSK-3 inactivation does not correlate with the extent of Akt activation mediated by insulin or IGF-1 receptors, indicating that the effect of insulin on GSK-3 requires additional kinases, and (iii) the pathways required for insulin stimulation of glycogen synthesis in mouse hepatocytes are PI 3-kinase-dependent and rapamycin-sensitive.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Cell Line
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Enzyme Activation / genetics
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Glycogen / biosynthesis*
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Glycogen Synthase / metabolism
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Glycogen Synthase Kinase 3
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Liver / cytology
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Liver / enzymology
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Liver / metabolism*
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Mice
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Mice, Knockout
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation
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Protein Kinase Inhibitors
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Protein Kinases*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins*
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Receptor, IGF Type 1 / physiology*
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Receptor, Insulin / deficiency
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Receptor, Insulin / genetics
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Receptor, Insulin / physiology*
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Ribosomal Protein S6 Kinases
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Sirolimus / pharmacology
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Wortmannin
Substances
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Androstadienes
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins
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Glycogen
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Glycogen Synthase
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Protein Kinases
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Receptor, IGF Type 1
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Receptor, Insulin
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Ribosomal Protein S6 Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3
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Sirolimus
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Wortmannin