Herein, interruption of IGF-1 receptor significantly abrogated the proliferative and anti-apoptotic effects of GLP-1. As AKT is one of the major kinases involved in IGF-1 receptor signaling pathway, we also examined the expression of IGF-1 receptor expression in both groups of mice which remained unchanged by exendin-4 treatment in both young and old mice. Taken together, we hypothesize that the increased AKT phosphorylation in the liver might be mediated through a signaling pathway different from that in the beta cells. In aged rodent models with dysglycemia, GLP-1 infusion augments insulin secretion and improves glycemic control. However, beta cell proliferation capability was attenuated with aging and treatment with exendin-4 only caused minimal mitosis in pancreatic islets of aged normal adult mice. Moreover, latest evidence showed very rarely observed beta cell proliferation and neogenesis in the human islets. The agerelated phenomena might be due to downregulation of key transcription factors and kinases implicated in beta cell survival and mitosis. In keeping with these findings, we also observed very slow rate of beta cell proliferation in the aging mice. Therefore, our findings and others suggest that the therapeutic effects of exendin-4 mediated through beta cell regeneration might not be clinically important in human adults. These evidence raised the concern that the effect of incretin based therapy on the beta cells might be affected by aging. Nevertheless, based on our data, we demonstrated that the glucose-lowering effects of exendin-4 were CZ415 preserved in aging nondiabetic mice. These data strongly supported that although exendin-4 mediated beta cell improvement might be affected by aging, the non-beta cell derived glucose lowering effects of exendin-4 therapy was still preserved, which maintained the therapeutic response of exendin-4 in aging diabetic patients. Exendin-4 reduced hepatic gluconeogenesis in young mice and enhanced insulin sensitivity in old mice, both resulted in normalized blood glucose. The lack of effects of exendin 4 on GLP1 and IGF1 receptors also suggest that other novel Eptapirone pathways may participate in the exendin-4 effect on the liver. These results offer new insights into the age-related changes in glucose metabolism which has bearing on the use of incretin-based therapy in elderly population.