Insulin activation of glycogen synthase in cultured human fibroblasts is not mediated solely via the insulin receptor.
Insulin binds to its specific cell surface receptor in cultured human fibroblasts and also stimulates the conversion of glycogen synthase from the glucose-6-phosphate (G-6-P) dependent to the G-6-P independent form. Although these two processes are tightly coupled in most target tissues for insulin action, in the fibroblast a variety of findings question the relationship of these two events to one another. In human fibroblasts the amount of insulin required to displace half of the 125I-insulin bound to the insulin receptor is 4 ng/ml (6.6 X 10(-10)M), but the activation of glycogen synthase is not maximal until 1-10 micrograms/ml with an ED50 of 30 ng/ml insulin. Antibodies directed against the insulin receptor, which activate glycogen synthase in both fat and muscle, do not stimulate the activation of glycogen synthase in the fibroblast. Fab fragments from anti-insulin receptor antibody compete for insulin binding, but do not inhibit the insulin-stimulated rise in independent activity. The insulin-like growth factor, MSA, which is 1% as potent as insulin in stimulating glucose oxidation in rat fat cells and in inhibiting 125I-insulin binding to human fibroblasts, is 25% as potent as insulin in stimulating glycogen synthase. Proinsulin is 2-10% as potent as insulin, but behaves as a "partial agonist" of insulin action in the fibroblast, i.e. proinsulin is able to elicit only 60% of the maximal response of insulin in the glycogen synthase assay, even at high concentrations. Finally, cell lines from patients with clearly defective insulin receptors exhibit normal insulin dose response curves for the activation of glycogen synthase.(ABSTRACT TRUNCATED AT 250 WORDS)
D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism*; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance; D007335:Insulin-Like Growth Factor II / Q000378:metabolism / Q000494:pharmacology; D011972:Receptor, Insulin / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
D007140:Immunoglobulin Fab Fragments; D007328:Insulin; D007335:Insulin-Like Growth Factor II; D006006:Glycogen Synthase; D011972:Receptor, Insulin