We have previously produced transgenic G-InsKi mice, a model allowing regulated portal insulin delivery from gastric G cells without using beta cells. Here, we report that in G-InsKi mice portal levels of transgenic human insulin are 6-fold higher than in peripheral circulation. Peptone-induced release of transgenic human insulin from G cells preferentially stimulated signaling cascades in the liver rather than in peripheral insulin-sensitive tissues, as judged by tyrosine phosphorylation of insulin receptor beta subunit and phosphorylation of protein kinase Akt/PKB at Thr-308. G-InsKi mice provide a novel animal model for elucidating direct effects of insulin on liver functions. (c) 2007 Published by Elsevier Inc.