Alteration in pancreatic immunoreactivity of insulin-like growth factor (IGF)-binding protein (IGFBP)-6 and in intracellular degradation of IGFBP-3 in fibroblasts of IGF-II receptor/IGF-II-deficient mice

The Type-2 insulin-like growth factor receptor (IGF2R) mediates the transpo rt of lysosomal hydrolases to lysosomes and the clearance of insulin-like g rowth factor II (IGF-II). Mutant mice lacking IGF2R usually die perinatally , but are completely rescued from lethality in the absence of ICF-II. IGF2R /IGF-II-deficient mice have elevated levels of circulating IGF binding prot ein (IGFBP)-3 and show a strong IGFBP-6 immunoreactivity in all pancreatic islet cells and in secretory granules of different size in acinar cells and interlobular connective tissue of exocrine pancreas. Fibroblasts derived f rom double mutant mice missort the lysosomal protease cathepsin D, and are able to degrade endocytosed (I-125)IGFBP-3 intracellularly, however, with l ower efficiency than in control cells. These results show that the deficien cy of IGF2R and ICF-II affects the expression and metabolism of IGFBPs in a tissue- and cell type-specific manner.