Metabolic actions of insulin-like growth factor II in cultured adult rat hepatocytes are not mediated through the insulin-like growth factor II receptor

Abstract

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.

IGF‐I, IGF‐II, and IGF‐receptor‐1 transcript and IGF‐II protein expression in myostatin knockout mice tissues

“…Although myostatin knockout kidney weight was not measured in the current and previous studies,15 increased IGF‐II levels may have caused the decline in IGF‐R1 mRNA expression to maintain proper size of myostatin knockout mice kidney. Several studies, however, have suggested that metabolic actions of IGF‐II, unlike its mitogenic actions, are not mediated through IGF‐R1 but through insulin receptors, to which IGF‐II can bind with low affinity 6, 9. Additionally, IGF‐II, but neither insulin nor IGF‐I, stimulated Na + −H + exchange across the brush‐border membrane of proximal tubular cells 17.…”

An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth

“…It is not clear how IGF2 exerts its activity on cartilage development. IGF2 is capable of binding to IGF1R, IGF2R and the insulin receptor (IR; INSR), although its affinity to IR is low (Hartmann et al, 1992). Additionally, their activities are modulated by various IGF-binding proteins (Fisher et al, 2005).…”

Characterization of the IGF axis components in isolated rat hepatic stellate cells

“…[1][2][3] A number of studies have indicated that most of the metabolic and mitogenic effects of IGF-I and -II are mediated by the IGF-I and insulin receptors. [4][5][6] The role of the mannose 6-phosphate/IGF-II receptor for transport of lysosomal enzymes and for binding and internalization of IGF-II is well characterized, but its role in signal transduction in response to IGF-II is still being debated. 7,8 IGF actions are determined by the availability of free IGFs to interact with receptors for IGF or insulin.…”