Other researcher proposed expression of GLP-1R in both human hepatocyte tissue and cell lines in the regulation of incretin effects in the liver. However, the existence of GLP-1 receptor in rodent liver is still very controversial. According to our data, the insulin secretion level was not significantly altered by exendin-4 treatment, and as the animals were sacrificed at least 12 hours after exendin-4 treatment, the insulinotrophic effect of exendin-4 could be excluded. Therefore, the increased AKT/FOXO1 phosphorylation was less CHS-828 inhibitor likely mediated by insulin. One explanation for the in vivo effects of exendin-4 on the liver is the inhibited glucagon secretion. Therefore, we tested the serum glucagon level in four groups of mice, the results showed that although the serum glucagon level was significantly increased by aging, it was not inhibited by exendin-4 treatment in both young and aging mice. In addition, liver AMPK, which has been reported to be phosphorylated by serum glucagon, was not altered by exendin-4 treatment in both groups of mice.These data suggested that glucagon might not participate in the glucose modulating effect of exendin-4 in our models. Another potential explanation is increased somatostatin. Somatostatin secretion has been reported to be stimulated by exendin- 4. The glucose modulating mechanism of somatostatin based therapy was contraversial, several previous studies showed that somatostatin normalized blood glucose potentially by inhibiting glucagon secretion. However in our system, the glucagon level was not significantly altered. Therefore increased somatostatin was less likely to participate in the improved glucose response in our model. But we currently do not have ELISA data to exclude this possibility. Since incretin receptor expression level is tightly regulated by prevailing blood glucose level at least in the pancreatic islets of human and rodents, it Pembrolizumab remains plausible that the inhibitory effect of incretin therapy on hepatic gluconeogenesis might be due to changes in other receptors or pathways yet to be identified. Other researchers have shown that GLP-1 increased beta cell proliferation by regulating IGF-1 receptor expression in the beta cells.