INSULIN-LIKE GROWTH FACTOR-II AND TRANSFORMING GROWTH-FACTOR-ALPHA INDEVELOPING HUMAN FETAL PANCREATIC-ISLETS

To understand the development of the human pancreas better, we studied the expression and regulation of insulin, insulin-like growth factor- II (IGF-II) and transforming growth factor-alpha (TGF-alpha) genes in the human fetal pancreas and islet-like cell clusters (ICC) from the s econd trimester human fetuses. Northern blot analysis revealed an abun dant expression of IGF-II, insulin and TGF-alpha mRNAs in the intact p ancreas and the cultured ICCs. Furthermore, transcripts for insulin re ceptor, type-I and -2 IGF receptors, and GH receptor could be amplifie d by polymerase chain reaction analysis from the pancreas and the ICCs . With in-situ hybridization, IGF-II mRNA was found in abundance in bo th the exocrine and endocrine pancreas, exceeding the amount of insuli n mRNA. In ICCs, insulin mRNA-containing cells were present as small c lusters in the periphery and in the centre of the clusters correspondi ng to the immunolocation of insulin. The ICCs also contained many epid ermal growth factor-, insulin- and type-I IGF receptor- and TGF-alpha- positive cells. When the ICCs were cultured in the presence of various secretagogues, only dibutyryl cyclic AMP was found to up-regulate ins ulin mRNA (39%; P<0.05). IGF-II mRNA was also under cyclic AMP-depende nt regulation (threefold increase; P=0.025). Furthermore, blocking the type-1 IGF receptor with a monoclonal receptor antibody drastically r educed insulin expression (87%; P=0.005) and additionally down-regulat ed IGF-II mRNA (49%; P=0.005). IGF-I, IGF-II, TGF-alpha or epidermal g rowth factor-receptor antibody had no significant effect on either ins ulin or IGF-II mRNA. Exogenous TGF-alpha inhibited the release of insu lin by the ICCs. It was concluded that IGF-II and TGF-alpha may be inv olved in the regulation of islet growth and differentiation.