AGE-ASSOCIATED ATTENUATION OF PANCREATIC β-CELL REGENERATION DEPENDS ON PI3K/AKT SIGNALING, ACTING THROUGH PANCREATIC AND DUODENAL HOMEOBOX-1 (PDX-1).

Abstract

Introduction: Although age-associated attenuation of β-cell regeneration has been reported, the mechanism for this attenuation with aging is not known. Previously, we reported that activation of the PI3K/Akt pathway is an important pathway for PDX-1-mediated duct differentiation during pancreatic regeneration. The purpose of our present study was to determine the relationship between the PI3K/Akt pathway and the age-associated decrease in β-cell regeneration after partial pancreatectomy (Px). Methods: Young (4-mo) and aged (24-mo) male C57BL/6 mice underwent 75% Px. Mice were sacrificed 0, 3 and 7 days after Px and the remnant pancreas was resected; expression of phosphorylated-Akt (pAkt) and PDX-1 was measured in remnant pancreas by Western blot or immunohistochemistry, respectively. Next, pancreatic duct cells were isolated from young and aged mice and pAkt and PDX-1 expression was determined by Western blot analysis. Duct cells from young mice were treated with wortmannin (100 nM), a selective PI3K inhibitor, and pAkt and PDX-1 expression was assessed by Western blot analysis. Results: The basal level of PDX-1 in the remnant pancreas was lower in aged mice than in young mice. PDX-1 expression in the remnant pancreas from young mice increased after Px, whereas no increase in the PDX-1 was noted in the aged mice. The level of pAkt was increased in pancreatic duct cells in young mice following Px compared with aged mice. Expression of PDX-1 was strongly detected in pancreatic duct cells in young mice, but not aged mice, following Px. Both PDX-1 and pAkt expression in duct cells in vitro from aged mice was significantly lower than that noted in young mice. PDX-1 and pAkt expression in duct cells was completely blocked by wortmannin treatment. Conclusions: Our results demonstrate that age-associated attenuation of pancreatic regeneration depends on PDX-1 expression which is regulated by the PI3K/Akt pathway. Importantly, we identify PDX-1 as a critical downstream target of the PI3K/Akt pathway in the pancreas.