Downregulation occurs normally in cultured Epstein-Barr virus-transformed lymphocytes from patients with extreme insulin resistance. Discrepancy between downregulation in vivo and in vitro.
Levels of fasting plasma insulin are generally inversely correlated with 125I-insulin binding to circulating blood cells. In disease states associated with hyperinsulinemia (e.g., obesity and non-insulin-dependent diabetes mellitus), 125I-insulin binding is usually low. In contrast, 125I-insulin binding to circulating cells may be normal in patients with certain forms of extreme insulin resistance despite marked hyperinsulinemia. To explain this paradox, it has been proposed that postbinding defects in insulin action may give rise to defects in downregulation. We have employed cultured Epstein-Barr virus (EBV)-transformed lymphocytes from eight patients with extreme insulin resistance to address the question of whether there is a defect in the downregulation process in vitro. In this cell type, insulin leads to a decrease in the number of insulin receptors on the cell surface by accelerating the rate of degradation of insulin receptors. We could not detect any abnormality in in vitro down-regulation with cultured EBV-transformed lymphocytes from insulin-resistant patients. The apparent discrepancy between the in vivo and in vitro studies raises the possibility that some factor in the patient's internal milieu may prevent insulin-induced downregulation. An alternative possible explanation might be that the mechanism of downregulation in vitro differs from the mechanism whereby receptor number is regulated in vivo in insulin's target cells.
D000293:Adolescent; D000328:Adult; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D002675:Child, Preschool; D003923:Diabetes Mellitus, Lipoatrophic / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004392:Dwarfism / Q000097:blood; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007223:Infant; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance; D007700:Kinetics; D008060:Lipodystrophy / Q000097:blood; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism*; D013577:Syndrome
D007328:Insulin; D011972:Receptor, Insulin