title: Antagonistic effects of a covalently dimerized insulin derivative on insulin receptors in 3T3-L1 adipocytes.
abstract: In the present study we describe the antagonistic effects of the covalently dimerized insulin derivative B29,B29'-suberoyl-insulin on insulin receptors in 3T3-L1 mouse cells. In differentiated 3T3-L1 adipocytes, the derivative fully inhibits binding of 125I-labeled insulin to its receptor with about the same affinity as unlabeled insulin. In contrast, the dimerized derivative only partially (approximately 20%) mimics insulin's effects on glucose transport and DNA synthesis in the absence of insulin. In the presence of insulin, the agent competitively inhibits insulin-stimulated DNA synthesis ([3H]thymidine incorporation into total DNA), glucose transport activity (2-deoxyglucose uptake rate), and insulin receptor tyrosine kinase activity. In rat adipocytes, in contrast, the dimerized derivative stimulates glucose transport (initial 3-O-methylglucose as well as 2-deoxyglucose uptake rates) to the same extent as insulin does, and it fails to inhibit the effect of insulin. The data indicate that the dimerized insulin derivative B29,B29'-suberoyl-insulin is an insulin receptor antagonist (partial agonist) which retains a moderate intrinsic activity. The effects of this agent reveal a striking difference in insulin receptor-mediated stimulation of glucose transport between 3T3-L1 fatty fibroblasts and the mature rat adipocyte.
authors.affiliation: Institut für Pharmakologie und Toxikologie, Universität Göttingen, Federal Republic of Germany.
authors.forename: M
authors.initials: M
authors.lastname: Weiland
authors.forename: C
authors.initials: C
authors.lastname: Brandenburg
authors.forename: D
authors.initials: D
authors.lastname: Brandenburg
authors.forename: H G
authors.initials: HG
authors.lastname: Joost
mesh_terms: D019325:3-O-Methylglucose; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002454:Cell Differentiation; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008757:Methylglucosides / Q000378:metabolism; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism; D017451:Receptors, Somatomedin
chemical_list: D007328:Insulin; D008757:Methylglucosides; D011956:Receptors, Cell Surface; D017451:Receptors, Somatomedin; C034329:insulin dimers; D019325:3-O-Methylglucose; D007334:Insulin-Like Growth Factor I; D011972:Receptor, Insulin