Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells

Insulin signaling is mediated by a complex network of diverging and converg ing pathways, with alternative proteins and isoforms at almost every step i n the process. We show here that insulin activates the transcription of its own gene and that of the 8 cell glucokinase gene (PGK) by different mechan isms. Whereas insulin gene transcription is promoted by signaling through i nsulin receptor A type (Ex11-), PI3K class la, and p70s6k, insulin stimulat es the PGK gene by signaling via insulin receptor B type (Ex11+), PI3K clas s Ii-like activity, and PKB (c-Akt). Our data provide evidence for selectiv ity in insulin action via the two isoforms of the insulin receptor, the mol ecular basis being preferential signaling through different PI3K and protei n kinases.