ABSTRACT
Maintenance of pancreatic ß-cell mass and function is fundamental to glucose homeostasis and to prevent diabetes. The PI3 K-Akt-mTORC1 pathway is critical for ß-cells mass and function, while PDX1 has been implicated in ß-cell development, maturation, and function. Here we tested whether Akt signaling requires PDX1 expression to regulate ß-cell mass, proliferation, and glucose homeostasis. In order to address that, we crossed a mouse model overexpressing constitutively active Akt mutant in ß-cells (ß-caAkt) with mice lacking one allele of PDX1gene (ß-caAkt/pdx1+/-). While the ß-caAkt mice exhibit higher plasma insulin levels, greater ß-cell mass and improved glucose tolerance compared to control mice, the ß-caAkt/pdx1+/- mice are hyperglycemic and intolerant to glucose. The changes in glucose homeostasis in ß-caAkt/pdx1+/- were associated with a 60% reduction in ß-cell mass compared to ß-caAkt mice. The impaired ß-cell mass in the ß-caAkt/pdx1+/- mice can be explained by a lesser ß-cell proliferation measured by the number of Ki67 positive ß-cells. We did not observe any differences in apoptosis between ß-caAkt/pdx1+/- and ß-caAkt mice. In conclusion, PDX1 contributes to ß-cell mass expansion and glucose metabolism induced by activation of Akt signaling.
