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Atrial Natriuretic Peptide Promotes Pancreatic Islet β-Cell Growth and Akt/Foxo1a/Cyclin D2 Signaling

Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York 14214

Address all correspondence and requests for reprints to: Dr. S. Laychock, 102 Farber Hall, Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14214. E-mail: laychock{at}buffalo.edu.

The adult differentiated insulin-secreting pancreatic islet β-cell experiences slow growth. This study shows that atrial natriuretic peptide (ANP) stimulates cell proliferation and [³H]thymidine incorporation in INS-1E glucose-sensitive rat β-cell line cells and isolated rat islet DNA. In addition, cGMP, the second messenger of natriuretic peptide receptors (NPR) A and B, stimulated islet DNA biosynthesis. The NPR-A receptor was expressed in INS-1E cells and islets. ANP-stimulated INS-1E cell DNA biosynthesis was blocked by preincubation with LY294002 (50 µM), an inhibitor of phosphatidylinositol 3'-kinase (PI3K). An indicator of cell cycle progression, cyclin D2 mRNA was increased by 2- to 3-fold in ANP- or 8-Br-cGMP-treated INS-1E cells and islets, and these responses were inhibited by LY294002. ANP and 8-Br-cGMP stimulated the phosphorylation of Akt and Foxo1a in INS-1E cells and islets, and LY294002 inhibited these responses. In contrast, ANP reduced the levels of phospho-ERK in INS-1E cells. Pancreas duodenum homeobox-1 (PDX-1) is essential for pancreas development, insulin production, and glucose homeostasis, and ANP increased PDX-1 mRNA levels by 2- to 3-fold in INS-1E cells and islets. The levels of glucokinase mRNA in islets and INS-1E cells were also increased in response to ANP. The evidence suggests that pancreatic β-cell NPR-A stimulation results in activation of a growth-promoting signaling pathway that includes PI3K/Akt/Foxo1a/cyclin D2. These data support the conclusion that the activation of Akt by ANP or 8-Br-cGMP promotes cyclin D2, PDX-1, and glucokinase transcription by phosphorylating and restricting Foxo1a activity.