Atrial Natriuretic Peptide (ANP) Activates Pancreatic Islet Phosphatidylinositol‐3′‐Kinase (PI3K)/Akt/FoxO1a/Cyclin D2 Signaling

Abstract

A link has been made between ANP and diabetes mellitus since hyperglycemia and diabetes are associated with elevated ANP levels. Natriuretic peptide receptor (NPR)‐A and NPR‐B mRNAs were detected in insulin secreting INS‐1E insulinoma cells and isolated rat pancreatic islets, but only NPR‐A protein was expressed on islet α‐and β‐cells. Culture of INS‐1E cells and islets with ANP (0.01–1 μM) increased cell proliferation, DNA biosynthesis and cyclin D2 mRNA levels. An analogue of cGMP, the second messenger of NPR‐A, also elevated DNA biosynthesis and cyclin D2 mRNA levels. Enhanced DNA biosynthesis and cyclin D2 mRNA induced by ANP were inhibited by LY294002, an inhibitor of PI3K. ANP and 8‐bromo‐cGMP also stimulated the phosphorylation of Akt (387±10% of control (P<0.05)) and its downstream target forkhead box O1a (FoxO1a) (175±11% of control (P<0.05)), a transcriptional repressor of cyclin D2; LY294002 inhibited these responses. The transcription of pancreas duodenum homeobox‐1 (PDX‐1) and glucokinase regulated by FoxO1a was increased 2‐ to 3‐fold with ANP present. The evidence suggests that NPR‐A stimulation results in activation of a growth promoting signaling pathway in the pancreatic β‐cell that includes PI3K/Akt/FoxO1a/cyclin D2. The activation of PI3K/Akt by ANP or 8‐bromo‐cGMP promotes cyclin D2, PDX‐1 and glucokinase transcription by phosphorylating and restricting FoxO1a activity.