Abstract
We recently reported that insulin and endothelin-1 (ET-1) can stimulate GLUT4 translocation via the heterotrimeric G protein G alpha q/11 and through PI3-kinase--mediated pathways in 3T3-L1 adipocytes. Because both hormones stimulate glucose transport through a common downstream pathway, we determined whether chronic ET-1 pretreatment would desensitize these cells to acute insulin signaling. We found that ET-1 pretreatment substantially inhibited insulin-stimulated 2-deoxyglucose uptake and GLUT4 translocation. Cotreatment with the ETA receptor antagonist BQ 610 prevented these effects, whereas inhibitors of G alpha i or G beta gamma were without effect. Chronic ET-1 treatment inhibited insulin-stimulated tyrosine phosphorylation of G alpha q/11 and IRS-1, as well as their association with PI3-kinase and blocked the activation of PI3-kinase activity and phosphorylation of AKT: In addition, chronic ET-1 treatment caused IRS-1 degradation, which could be blocked by inhibitors of PI3-kinase or p70 S6-kinase. Similarly, expression of a constitutively active G alpha q mutant, but not the wild-type G alpha q, led to IRS-1 degradation and inhibited insulin-stimulated phosphorylation of IRS-1, suggesting that the ET-1-induced decrease in IRS-1 depends on G alpha q/11 and PI3-kinase. Insulin-stimulated tyrosine phosphorylation of SHC was also reduced in ET-1 treated cells, resulting in inhibition of the MAPK pathway. In conclusion, chronic ET-1 treatment of 3T3-L1 adipocytes leads to heterologous desensitization of metabolic and mitogenic actions of insulin, most likely through the decreased tyrosine phosphorylation of the insulin receptor substrates IRS-1, SHC, and G alpha q/11.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Adaptor Proteins, Signal Transducing
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Adipocytes / drug effects*
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Adipocytes / metabolism
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Animals
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Biological Transport / drug effects
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Deoxyglucose / metabolism
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Drug Interactions
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Endothelin Receptor Antagonists
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Endothelin-1 / pharmacology*
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GTP-Binding Protein alpha Subunit, Gi2
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GTP-Binding Protein alpha Subunits, Gi-Go / antagonists & inhibitors
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GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
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GTP-Binding Protein alpha Subunits, Gq-G11
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Glucose Transporter Type 4
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Heterotrimeric GTP-Binding Proteins / antagonists & inhibitors
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Heterotrimeric GTP-Binding Proteins / metabolism
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Insulin / pharmacology*
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Intramolecular Transferases / metabolism
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Monosaccharide Transport Proteins / metabolism
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Muscle Proteins*
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Oligopeptides / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Protein-Serine-Threonine Kinases*
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-cbl
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Receptor, Endothelin A
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Signal Transduction / drug effects
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Tyrosine / metabolism
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Ubiquitin-Protein Ligases*
Substances
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Adaptor Proteins, Signal Transducing
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Endothelin Receptor Antagonists
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Endothelin-1
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Gab1 protein, mouse
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Glucose Transporter Type 4
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Insulin
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Insulin Receptor Substrate Proteins
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Intracellular Signaling Peptides and Proteins
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Irs1 protein, mouse
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Irs2 protein, mouse
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Monosaccharide Transport Proteins
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Muscle Proteins
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Oligopeptides
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Phosphoproteins
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Proto-Oncogene Proteins
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Receptor, Endothelin A
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Slc2a4 protein, mouse
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BQ 610
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Tyrosine
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Deoxyglucose
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases
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Protein-Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Mitogen-Activated Protein Kinases
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GTP-Binding Protein alpha Subunit, Gi2
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GTP-Binding Protein alpha Subunits, Gi-Go
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GTP-Binding Protein alpha Subunits, Gq-G11
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Gnai2 protein, mouse
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Heterotrimeric GTP-Binding Proteins
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Intramolecular Transferases
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squalene-hopene cyclase
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CBL protein, human
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Cbl protein, mouse