title: Identification of a major defect in insulin-resistant tissues of genetically obese (fa/fa) rats. Impaired protein kinase C.
abstract: In perfused lean rat hearts, the activator of protein kinase C phorbol myristate acetate (PMA), when present alone, stimulates glucose transport but inhibits the insulin stimulation of this transport. PMA also inactivates glycogen synthase in hepatocytes. In contrast, none of these effects are observed in hearts and hepatocytes of obese animals, indicating an impaired protein kinase C activation in these tissues, which are insulin resistant. Direct measurements of protein kinase C activity in lean rat hearts revealed that PMA provokes a translocation of the enzyme from a soluble to a particulate fraction. In obese rat hearts, the basal distribution of protein kinase C is altered (more activity is found in the soluble and less in the particulate fraction), and the translocation induced by PMA is impaired. Pretreatment of lean rats with PMA in vivo, aimed at downregulating protein kinase C, induces the same defects (i.e., insulin resistance and unresponsiveness to PMA) as those observed in hearts of untreated obese animals. The results indicate that part of the insulin resistance might be the consequence of altered modulation of insulin action by protein kinase C.
mesh_terms: D019325:3-O-Methylglucose; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007333:Insulin Resistance / Q000235:genetics*; D008757:Methylglucosides / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D009765:Obesity / Q000235:genetics*; D011493:Protein Kinase C / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D051381:Rats; D011922:Rats, Mutant Strains / Q000378:metabolism*; D011924:Rats, Zucker / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D008757:Methylglucosides; D019325:3-O-Methylglucose; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate