Pioglitazone promotes insulin-induced activation of phosphoinositide 3-kinase in 3T3-L1 adipocytes by inhibiting a negative control mechanism
| Autor: | John E. Bleasdale, Craig L. Smith, Karen M. Sizer, Michael L. Swanson, Cynthia S. Jacob |
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| Rok vydání: | 1994 |
| Předmět: |
Male
medicine.medical_specialty medicine.drug_class medicine.medical_treatment Biology Biochemistry Phosphatidylinositol 3-Kinases Mice chemistry.chemical_compound Endocrinology Adipocyte Internal medicine Adipocytes Cyclic AMP medicine Animals Hypoglycemic Agents Insulin Insulin-Like Growth Factor I Thiazolidinedione Phosphotyrosine 1-Phosphatidylinositol 4-Kinase Molecular Biology Immunosorbent Techniques Phosphoinositide 3-kinase Pioglitazone Isoproterenol Cell Differentiation 3T3-L1 3T3 Cells Precipitin Tests Enzyme Activation Mice Inbred C57BL Kinetics Phosphotransferases (Alcohol Group Acceptor) Thiazoles Mechanism of action chemistry 3' 5'-Cyclic-AMP Phosphodiesterases biology.protein Tyrosine Thiazolidinediones medicine.symptom Signal transduction medicine.drug |
| Zdroj: | Molecular and Cellular Endocrinology. 102:119-129 |
| ISSN: | 0303-7207 |
| Popis: | Activation of phosphoinositide 3-kinase (PI 3-kinase) is an early event in insulin signal transduction that is blocked completely in adipocytes from insulin-resistant KKAy mice. Treatment of KKAy mice with pioglitazone, an anti-diabetic thiazolidinedione, partially restores insulin-dependent changes in PI 3-kinase. The mechanism of this effect of pioglitazone was investigated, using murine 3T3-L1 cells as an experimental model. Insulin and insulin-like growth factor I (IGF-I) each elicited rapid (within 2 min) and large (2- to 5-fold) increases in PI 3-kinase activity that could be immunoprecipitated using anti-phosphotyrosine (pY) antibodies. Maximal insulin-induced activity of PI 3-kinase in pY-immunoprecipitates was similar in 3T3-L1 adipocytes and mouse adipocytes, but the kinetics of activation differed. Insulin- and IGF-I-induced changes in PI 3-kinase were each half-maximal at 3-5 nM of hormone and were not additive. Increases in both insulin-induced and IGF-I-induced pY-immunoprecipitable PI 3-kinase activity were observed when 3T3-L1 fibroblasts became confluent and when they adopted the adipocyte phenotype. Pioglitazone (10 microM), administered either acutely or chronically to either 3T3-L1 adipocytes or 3T3-L1 fibroblasts, did not alter greatly the kinetics, magnitude or sensitivity of changes in PI 3-kinase elicited by either insulin or IGF-I. In contrast, the attenuation by isoproterenol of insulin-induced changes in PI 3-kinase was prevented in cells pretreated with pioglitazone. This effect of pioglitazone did not involve inhibition of isoproterenol-elicited accumulation of cyclic AMP. Pioglitazone also prevented attenuation of insulin induced changes in PI 3-kinase by cell penetrating analogs of cyclic AMP. Pioglitazone, therefore, has no direct effect on insulin-stimulated PI 3-kinase activity, but interferes with a cyclic AMP-dependent mechanism that normally antagonizes this action of insulin. These data support the proposition that the facilitation of insulin action by pioglitazone involves, at least in part, an inhibition of a negative control mechanism. |
| Databáze: | OpenAIRE |
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