In addition, in both young and aging mice, we did not observe significant increase in AKT phosphorylation after exendin-4 treatment. Previous studies in young diabetic animal models suggested exendin-4 augmented beta cell function. However, as beta cell proliferation and insulin secretion were highly correlated with circulation glucose and lipid, it is therefore difficult to identify the non-beta cell effects due to improvement in glucose and lipid profile. Also, it is not easy to clarify whether the increased beta cell mass, which have been found in multiple diabetic rodent models after exendin-4 treatment, was due to increased beta cell proliferation or decreased beta cell apoptosis or both. In contrast to the diabetic mice models, the non-diabetic mice showed normal glycemic control and islet morphology with very rare TUNEL positive cells in the panreatic islets. In addition, as beta cell proliferation rate is very low, it was reasonable that 10 days�� treatment was not enough to trigger obvious islet expansion in normal adult mice. In support of this, we only found significant increase in beta cell mass expansion 4 weeks after the exendin-4 intervention in the pancreatectomized rat model. Indeed, in 2 months old mice, 21 days�� treatment with both 10 nM and 24 nM exendin-4 significantly increased beta cell proliferation, but 10 days�� injection with both dosages showed no obvious effect,which suggested that exendin-4 only triggered beta cell proliferation after relatively chronic treatment in young mice. Therefore, 10 nM exendin-4 treatment for 10 days in both young and aging mice was appropriate to study the extrapancreas effects of GLP-1 mimetics. This result is consistent with previously published literature.. Recently, the blood glucose lowering effects of exendin-4 independent of beta cells have attracted much attention. In in vitro experiments, exendin-4 enhanced insulin signaling Dimethylcurcumin pathway although it remains to be confirmed in in vivo conditions. In our experiment, the ITT results showed significantly improved insulin 7-Deazaadenosine sensitivity in aging mice but not in the 3-months old young mice after exendin-4 treatment. This result was reasonable because the insulin sensitivity in 3-months group was already very ideal comparing to the aging mice. To explain how exendin-4 lowered glucose in those young adult mice, we checked the liver glucose metabolism after exendin-4 treatment in 3 months old mice.