Atrial Natriuretic Peptide Stimulates Rat Pancreatic Beta‐Cell Growth

Abstract

Natriuretic peptide receptor‐A (NPR‐A) is a guanylyl cyclase‐linked receptor that generates cGMP in response to atrial natriuretic peptide (ANP). Since elevated ANP levels are associated with diabetes mellitus and hyperglycemia, ANP effects on cultured isolated rat pancreatic islets and insulinoma cells (INS‐1e) were determined. Islets and INS‐1e cells expressed NPR‐A mRNA and protein. To determine the chronic effects of ANP, islets were cultured at 5.5 mM glucose with ANP (1 μM) for 7 days, which increased [3H]thymidine incorporation to 200±36% of control (p<0.05); similarly, ANP increased INS‐1e cell [3H]thymidine incorporation to 163±18% of control (p<0.05). 8‐Bromo‐cGMP (0.5 mM) also stimulated islet [3H]thymidine incorporation to 207±15% of control (p<0.001). The mTOR inhibitor rapamycin failed to inhibit ANP‐stimulated [3H]thymidine incorporation. In ANP‐treated INS‐1e cells, the phosphatidylinositol 3‐kinase (PI3K)/Akt/Foxo1a pathway was activated. Phospho‐Akt and phospho‐Foxo1a were increased by 387±77% and 170 ±12% of control (p<0.05), respectively, and this response was blocked by the PI3K inhibitor LY294002. Cyclin D2 mRNA was upregulated in ANP treated islets and INS‐1e cells by 336±71% and 332±36% of control (p<0.05), respectively. The evidence suggests that the mitogenic response stimulated by ANP treatment involves activation of the PI3K/Akt/Foxo1a/cyclin D2 pathway.