Absence of insulin-receptor downregulation in hepatocytes from hyperinsulinemic rats.
Insulin-induced downregulation of the insulin receptor occurs in conditions associated with high extracellular concentrations of insulin. This paper describes the effect of experimental hyperinsulinemia on insulin binding to isolated hepatocytes. In vivo experimental hyperinsulinemia was produced in rats by subcutaneous injection of long-acting insulin at low (10 mU.g-1.day-1), medium (up to 25 mU.g-1.day-1), and high (up to 50 mU.g-1.day-1) doses over 1 or 2 wk. Insulin-stimulated lipogenesis was measured to determine the efficacy of the experimentally produced hyperinsulinemia. The results showed that 1) insulin-induced downregulation, determined by insulin binding, was not present in hepatocytes from any of the hyperinsulinemic rats; 2) insulin binding was increased in hepatocytes from 1- and 2-wk high-dose hyperinsulinemic rats compared with 1-wk sucrose-control (P less than 0.05), 2-wk sucrose-control (P less than 0.01), and normal rats (P less than 0.01); 3) increased binding may have been due to an increase in the number of low-affinity receptors; 4) insulin's effect on lipogenesis (i.e., insulin-stimulated lipogenesis minus the basal value) was increased in either 1-wk (P less than 0.001) or 2-wk (P less than 0.001) high-dose insulin-treated rats compared with either normal or 2-wk sucrose-control rats; 5) insulin's effect on hepatocyte lipogenesis in sucrose-control (P less than 0.025) and in all other insulin-treated (P less than 0.008 or P less than 0.05 for 2-wk medium dose) rats was greater than insulin's effect in normal hepatocytes. The reasons for the absence of downregulation are not clear, but rapid receptor recycling, rapid degradation, and upregulation are listed as possibilities.
Department of Clinical Biochemistry, Queen Elizabeth II Medical Center, Nedlands, Australia.
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Bottomley
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Garcia-Webb
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D006946:Hyperinsulinism / Q000378:metabolism*; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology; D049528:Insulin, Long-Acting; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D051381:Rats; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D013395:Sucrose / Q000494:pharmacology
D001786:Blood Glucose; D007328:Insulin; D049528:Insulin, Long-Acting; C023501:Insulin, Ultratard; D013395:Sucrose; D011972:Receptor, Insulin