Pancreatic and duodenal homeobox-1 (PDX1) contributes to β-cell mass expansion and proliferation induced by Akt/PKB pathway

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