Metabolic actions of insulin-like growth factor II in cultured adult rat hepatocytes are not mediated through the insulin-like growth factor II receptor.
Short- and long-term regulation of hepatic carbohydrate metabolism by insulin-like growth factor II was studied in primary cultures of adult rat hepatocytes and compared to the metabolic potency of insulin. Insulin-like growth factor II stimulated glycogen synthesis from [14C]glucose, uptake of [3H]aminoisobutyric acid and [14C]lactate formation from [14C]glucose up to three-fold. Basal glycogenolysis was inhibited to about 10%, and glucagon-activated glycogenolysis was blocked completely. The enzymatic activity of glucokinase and pyruvate kinase was induced two-fold, the glucagon-dependent induction of phosphoenolpyruvate carboxykinase was antagonized. Compared to insulin, half-maximal responses required up to 50 times higher insulin-like growth factor II concentrations ranging from 10-20 nmol/l. A similar difference was observed for binding affinity of insulin-like growth factor II to the insulin receptor. The interaction with the insulin-like growth factor II/mannose 6-phosphate (IGF-II/Man-6-P) receptor was examined by studying 125I-insulin-like growth factor II binding and uptake of lysosomal enzymes. The affinity of insulin-like growth factor II to the IGF-II/Man-6-P receptor was considerably higher than for the insulin receptor. Antibodies against the IGF-II/Man-6-P receptor did not affect metabolic responses to insulin-like growth factor II, while binding to its receptor and the receptor-mediated endocytosis of arylsulphatase A were strongly inhibited. Thus, in adult rat liver insulin-like growth factor II appeared to exert metabolic actions not via interaction with its own receptor but through low affinity binding to hepatic insulin receptors.
Department of Medicine, Georg-August-Universität, Göttingen, FRG.
H
H
Hartmann
A
A
Meyer-Alber
T
T
Braulke
D000621:Aminoisobutyric Acids / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002553:Cerebroside-Sulfatase / Q000378:metabolism; D004790:Enzyme Induction; D005941:Glucokinase / Q000096:biosynthesis; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008112:Liver Glycogen / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D008360:Mannosephosphates / Q000378:metabolism; D011770:Pyruvate Kinase / Q000096:biosynthesis; D051381:Rats; D011919:Rats, Inbred Strains; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology*
D000621:Aminoisobutyric Acids; D008112:Liver Glycogen; D008360:Mannosephosphates; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D007335:Insulin-Like Growth Factor II; D005941:Glucokinase; D011770:Pyruvate Kinase; D002553:Cerebroside-Sulfatase; D005947:Glucose