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